Use of anti-IL-36R antibodies to treat hidradenitis suppurativa (HS)

Abstract

The present invention provides methods, uses, and compositions for treating hidradenitis suppurativa. The present invention describes methods and uses for treating hidradenitis suppurativa with interleukin-36R (anti-IL36R) antibodies. It also describes methods for determining the effectiveness of anti-IL36R antibodies for treating hidradenitis suppurativa in a subject.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted via the Patent Center in XML format, the contents of which are incorporated herein by reference. The XML copy was created on March 1, 2024, is named 09-0743-WO-1_SL.xml, and is 135,435 bytes in size.

[0002] Technical field of the invention The present invention relates to the administration of an anti-interleukin-36 receptor (anti-IL-36R) antibody to a subject with hidradenitis suppurativa (HS) and the treatment and / or prevention of HS in a subject. More specifically, the present invention relates to the administration of spesolimab to a subject suffering from HS.

[0003] background Hidradenitis suppurativa (HS), also known as acne inversa, is a rare, chronic inflammatory skin disease characterized by recurrent, painful abscesses and fistulas (also called drainage channels). Patients with HS have the lowest objective quality of life of any skin disease. Lesions typically occur in the axilla, groin, inframammary, or anogenital areas of the body. HS lesions may progress to form fistulas and enlarging abscesses. Sequelae include significant pain, scarring, and psychological distress. The average age of onset is in the early 20s (Zouboulis CC, Marmol V del, Mrowietz U, et al. Hidradenitis suppurativa / acne inversa: criteria for diagnosis, severity assessment, classification, and disease evaluation. Dermatology (Basel) 2015;231(2):184-190).

[0004] The global prevalence of HS is reported to be 0.3% worldwide, varying between 0.2% and 0.6% depending on the region (Phan K, Charlton O, Smith SD. Global prevalence of hidradenitis suppurativa and geographical variation - systematic review and meta-analysis. Biomedical Dermatology. 2020;4(2):1-6). Underdiagnosis or inappropriate diagnosis is common. Overall, the prevalence of HS varies widely based on study methodology, but the disease is thought to be more common than previously thought (Saunte DM, Boer J, Stratigos A, et al. Diagnostic delay in hidradenitis suppurativa is a global problem. Br J Dermatol 2015;173(6):1546-1549).

[0005] Some of the most burdensome symptoms of HS from the patient's perspective are pain, pus drainage and explosive opening, itching, skin tightness (scarring), odor, fatigue, and flu-like symptoms. Patients are reported to be dissatisfied with the level of control provided by currently available treatment options. Unmet needs from the patient's perspective include the need for new medical treatments with good efficacy and tolerability profiles. Qualitative evidence indicated that the most important treatment goals from the patient's perspective were pain, pus drainage (including explosive opening), and fatigue.

[0006] Autoinflammation has been suggested to play a role in the pathogenesis. Although the exact cytokine profile in HS remains to be determined, abnormal levels of several inflammatory cytokines have been observed. TNFα protein levels were also elevated in these patients.

[0007] A genetic basis for HS has been identified in some families with a history of HS. The first mutations identified in families with HS are in γ-secretase, an endoprotease complex that cleaves multiple type 1 transmembrane proteins and is encoded by multiple genes, including NCSTN, PSENEN, and PSEN1. Loss-of-function mutations in the NCSTN gene (which encodes one of the four subunits of γ-secretase) support a critical role for the γ-secretase complex in HS. Although robust correlations between genotype and phenotype are lacking, the observed clinical phenotype is severe and widespread in NCSTN mutation-positive patients with HS.In most patients, HS is triggered by environmental factors in genetically predisposed individuals (Scala E et al. Hidradenitis Suppurativa: Where We Are and Where We Are Going. Cells 2021;10; van Straalen KR,et al. Contribution of Genetics to the Susceptibility to Hidradenitis Suppurativa in a Large, Cross-sectional Dutch Twin Cohort. JAMA Dermatol 2020;156:1359-62; Pink AE,et al. Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). Journal of Investigative Dermatology 2012;132:2459-61; Moltrasio C,et al. Hidradenitis Suppurativa: A Perspective on Genetic Factors Involved in the Disease. Biomedicines 2022;10;Gao M, Wang PG, Cui Y, et al. Inversa acne (hidradenitis suppurativa): a case report and identification of the locus at chromosome 1p21.1-1q25.3. J Invest Dermatol 2006;126:1302-6 and Nomura Y, Nomura T, Suzuki S, et al. A novel NCSTN mutation alone may be insufficient for the development of familial hidradenitis suppurativa. J Dermatol Sci 2014;74:180-2).

[0008] Treatment of HS often begins with topical or oral antibiotics, such as topical clindamycin and oral tetracycline, followed by rifampicin if no improvement is seen. If topical and oral antibiotics are ineffective or the disease progresses, biologics are recommended (Zouboulis CC, Desai N, Emtestam L, et al. European S1 guideline for the treatment of hidradenitis suppurativa / acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-644). The TNF-α antagonist adalimumab is the only approved biologic, but response rates are 42–59% with a q1w sc administration schedule, compared with 26–28% with placebo. Biologics are an emerging treatment modality used to manage many inflammatory conditions, including HS. Their use is typically reserved for moderate to severe cases or those refractory to treatment. Other biologics include, for example, infliximab (anti-TNF-α, one open-label phase II study with 17 patients), golimumab (anti-TNF-α, no clinical trials, only case reports), enteracept (soluble TNF receptor, double-blind study), ustekinumab (anti-IL-12 / IL-23, one open-label phase II study with 17 patients), guselkumab (anti-IL-23, phase II), risankizumab (anti-IL-23, phase II), and anakinra (anti-IL-1α, one open-label phase II study with 17 patients). Other agents being tested include rivaroxaban (anti-IL-1α, one double-blind randomized clinical trial (RCT) with 20 patients and one open-label clinical trial with 6 patients), bermekimab (anti-IL-1α, one double-blind randomized clinical trial (RCT) with 20 patients and one open-label clinical trial with 6 patients), secukinumab (anti-IL-17, clinical trials ongoing), bimekizumab (anti-IL-17A / F, a phase III trial that met its primary endpoint and demonstrated statistically significant, consistent, and clinically meaningful improvements), and brodalumab (anti-IL-17R, phase II ongoing) with limited results.However, recent results with bimekizumab and brodalumab, agents that target the IL-17 pathway, are indeed promising (Flood KS, Porter ML, Kimball AB. Biologic Treatment for Hidradenitis Suppurativa. Am J Clin Dermatol. 2019 Oct;20(5):625-638; Glatt S, Jemec GBE, Forman S, et al. Efficacy and Safety of Bimekizumab in Moderate to Severe Hidradenitis Suppurativa: A Phase 2, Double-blind, Placebo-Controlled Randomized Clinical Trial. JAMA Dermatol. 2021;157(11):1279-1288; Frew JW, Navrazhina K, Grand D, Sullivan-Whalen M, Gilleaudeau P, Garcet S, Ungar J, Krueger JG. The effect of Subcutaneous brodalumab on clinical disease activity in hidradenitis suppurativa: An open-label cohort study. J Am Acad Dermatol. 2020 Nov;83(5):1341-1348). If medical management is ineffective, surgery is the only option.

[0009] There is also research into the relationship between IL-36 and the pathogenesis of HS. However, recent clinical trials of an anti-IL-36R antagonist (imsidolimab) for treating moderate to severe hidradenitis suppurativa (HS) failed to demonstrate demonstrable improvement over placebo in the primary and key secondary endpoints for HS (see A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Subjects With Hidradenitis Suppurativa ClinicalTrials.gov NCT04856930; Anaptysbio Reports HARP Phase 2 Top-line Data of Imsidolimab in Moderate to Severe Hidradenitis Suppurativa, August 31, 2022).

[0010] Thus, there is a need in the art for new targeted therapies to treat and / or prevent hidradenitis suppurativa (HS).

[0011] Summary of the Invention Given the limited success in treating hidradenitis suppurativa (HS), particularly in view of the debilitating nature of this disease, there is a need for effective treatments. The present invention addresses this need by providing biological therapeutic agents, particularly antibodies, that bind to IL-36R as first, second, third, or subsequent line therapies for treating hidradenitis suppurativa.

[0012] In a first aspect, the present invention relates to a method for treating, preventing, or ameliorating hidradenitis suppurativa (HS) in a subject, comprising administering to the subject or having administered to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof, hi an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0013] In a second aspect, the present invention relates to treating moderate to severe HS in a patient, comprising administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0014] In a third aspect, the present invention relates to a method of treating a skin disorder associated with hidradenitis suppurativa (HS) in a patient, comprising administering to said patient or having administered to said patient a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0015] In a fourth aspect, the present invention provides a method for reducing or alleviating signs or symptoms of HS in a patient, the method comprising administering to the patient or having administered a therapeutically effective amount of an anti-IL-36R antibody. In an embodiment of this aspect, the present invention provides a method for reducing or alleviating the number, prevalence, severity, and / or recurrence of drainage ducts in an HS patient, the method comprising administering to the patient or having administered a therapeutically effective amount of an anti-IL-36R antibody. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0016] In a fifth aspect, the present invention relates to a method for treating skin inflammation associated with hidradenitis suppurativa (HS) in a subject, the method comprising administering to the subject or having administered to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab. In a related embodiment, the present invention relates to a method for preventing or ameliorating neutrophil infiltration in affected skin tissue of a subject suffering from hidradenitis suppurativa (HS), the method comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab. An embodiment of the present invention relates to a method for reducing susceptibility to skin infection in a subject with hidradenitis suppurativa (HS), the method comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody (as disclosed herein) or antigen-binding fragment thereof. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0017] In a sixth aspect, the present invention relates to a method for reducing the severity and duration of acute flares of hidradenitis suppurativa (HS), comprising administering to a patient or having administered to said patient a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0018] In embodiments of any of the first through sixth aspects, a second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody or antigen-binding fragment thereof. In related embodiments, the second therapeutic agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antifungal agent, another IL-36R antagonist, an anti-PDE4, an IL-17 antagonist, an IL-12 / IL-23 antagonist, an IL-23 antagonist and an IL-1 antagonist, an IgE inhibitor, a corticosteroid, an NSAID, an IL-4R antagonist, a TNF-α inhibitor, and an IFNγ.

[0019] In an embodiment related to any of the first to sixth aspects, 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); and 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).

[0020] In an embodiment related to any of the first to sixth aspects, 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); and 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: 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).

[0021] In an embodiment of any of the first to sixth aspects, the anti-IL-36R antibody is 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); and 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); or 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); and 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); or 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); and 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); or 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); and 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); or v) 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); and 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); or 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); and 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); 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); and 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: 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). Includes:

[0022] In an embodiment of any of the first to sixth aspects, the anti-IL-36R antibody is 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 Includes:

[0023] In an embodiment of any of the first to sixth aspects, the anti-IL-36R antibody is i. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or iv. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125, or v. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126, or vi. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or vii. a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or viii. A light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139, or ix. A light chain comprising the amino acid sequence of SEQ ID NO: 124 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 Includes:

[0024] In one embodiment of any of the first to sixth aspects, the present invention provides a method of treating a subject having hidradenitis suppurativa (HS), comprising administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, to treat HS according to a multiple variable dose schedule, wherein the multiple variable dose schedule comprises administering at least one or more parenteral (e.g., intravenous or subcutaneous) doses. In a related embodiment, the one or more parenteral doses each comprise at least 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, or 3000 mg of the anti-IL-36R antibody, wherein the total loading dose is at least 900 mg, 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2000 mg, 2400 mg, 2700 mg, 3000 mg, 3600 mg, 4800 mg, 6000 mg, 7200 mg, or 8000 mg. In a related embodiment, the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, wherein the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, or 1800 mg of the anti-IL-36R antibody. In related embodiments, the anti-IL-36R antibody is administered in 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 450 mg; 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 600 mg; 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 900 mg; 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 1200 mg; 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 1800 mg; 1, 2, 3, or 4 parenteral doses (qw, q2w, q4w) of 2000 mg; 1 or 2 parenteral doses (q2w, q4w) of 2400 mg; 1 or 2 parenteral doses (q2w, q4w) of 3000 mg, or any combination thereof to achieve an effective dose. In related embodiments, 1, 2, 3 or 4 parenteral doses are administered at 1 week (qw), 2 weeks (q2w) or 4 weeks (q4w) intervals.

[0025] In one embodiment of any of the first to sixth aspects, the present invention provides a method for treating a subject having hidradenitis suppurativa (HS), comprising administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, to treat HS according to a multiple variable dose schedule, wherein the multiple variable dose schedule comprises administering at least one or more intravenous doses. In a related embodiment, the one or more intravenous doses each comprise at least 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, or 3000 mg of the anti-IL-36R antibody, wherein the total loading dose is at least 900 mg, 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2000 mg, 2400 mg, 2700 mg, 3000 mg, 3600 mg, 4800 mg, 5400 mg, 6000 mg, 7200 mg, or 8000 mg. In a related embodiment, the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, wherein the loading dose comprises one or more intravenous doses of 450 mg, 600 mg, 900 mg, 1200 mg, or 1800 mg of the anti-IL-36R antibody. In related embodiments, the anti-IL-36R antibody is administered in one, two, three, or four intravenous doses (qw, q2w, q4w) of 450 mg; one, two, three, or four parenteral doses (qw, q2w, q4w) of 600 mg; one, two, three, or four intravenous doses (qw, q2w, q4w) of 900 mg; one, two, three, or four intravenous doses (qw, q2w, q4w) of 1200 mg; one, two, three, or four intravenous doses (qw, q2w, q4w) of 1800 mg; one, two, three, or four intravenous doses (qw, q2w, q4w) of 2000 mg; one or two intravenous doses (qw, q2w, q4w) of 2400 mg; one or two intravenous doses (q2w, q4w) of 3000 mg, or any combination thereof to achieve an effective dose.

[0026] In one embodiment of any of the first to sixth aspects, the present invention provides a method for treating a subject having hidradenitis suppurativa (HS), comprising administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, according to a multiple variable dose schedule to treat HS, wherein the multiple variable dose schedule comprises administering at least one or more subcutaneous doses. In a related embodiment, each of the one or more subcutaneous doses comprises at least 450 mg, 600 mg, 900 mg, 1200 mg, or 1800 mg, 2000 mg, or 3000 mg of said anti-IL-36R antibody, wherein the total loading dose is at least 900 mg, 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2000 mg, 2400 mg, 2700 mg, 3000 mg, 3600 mg, 4800 mg, 5400 mg, 6000 mg, 7200 mg, or 8000 mg. In a related embodiment, the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, wherein the loading dose comprises one or more subcutaneous doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 2000 mg of said anti-IL-36R antibody. In a related embodiment, the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, wherein the loading dose comprises one or more subcutaneous doses of 450 mg (qw, q2w, q4w); 1, 2, 3, or 4 subcutaneous doses (qw, q2w, q4w) of 600 mg; 1, 2, 3, or 4 subcutaneous doses (qw, q2w, q4w) of 900 mg; 1, 2, 3, or 4 subcutaneous doses (qw, q2w, q4w) of 1200 mg; 180 In a related embodiment, the 1, 2, 3, or 4 subcutaneous doses are administered at intervals of 1 week (qw), 2 weeks (q2w), or 4 weeks (q4w).

[0027] In one embodiment related to any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein the total loading dose is at least 1200 mg, 1800 mg, 3000 mg, 3600 mg, 6000 mg, 7200 mg, or 8000 mg. In a non-limiting exemplary embodiment, four intravenous doses of 450 mg are delivered at weeks 0, 1, 2, and 3 for a total loading dose of 1800 mg, four intravenous doses of 900 mg are delivered at weeks 0, 1, 2, and 3 for a total loading dose of 3600 mg, or four intravenous doses of 1800 mg are delivered at weeks 0, 1, 2, and 3 for a total loading dose of 7200 mg.

[0028] Table 1: Exemplary Loading Doses [Table 1]

[0029] In another embodiment of any of the first through sixth aspects, the subject is administered 1, 2, 3, or 4 intravenous doses as a loading dose, followed by at least 1, 2, 3, or 4 subcutaneous doses as maintenance doses, 4, 5, 6, 7, 8, 10, 12, or 16 weeks, 1, 2, or 4 week intervals (qw, q2w, q4w) after the last intravenous dose, e.g., after completion of the loading dose.

[0030] In another embodiment of any of the first through sixth aspects, the subject is administered 1, 2, 3, or 4 subcutaneous doses as a loading dose, followed by at least 1, 2, 3, or 4 subcutaneous doses as maintenance doses, at intervals of 4, 5, 6, 7, 8, 10, or 12, 16 weeks, 1, 2, or 4 weeks (qw, q2w, q4w) after the last subcutaneous dose, e.g., after completion of the loading dose.

[0031] In another embodiment of any of the first through sixth aspects, the subject is administered or has been administered an isolated human anti-IL-36R antibody, or antigen-binding portion thereof, according to a multiple variable dose regimen, wherein the multiple variable dose regimen comprises at least one, two, three, four intravenous or subcutaneous doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, 3000 mg. The method comprises administering a loading dose comprising at least one subcutaneous dose at 1, 2, or 4 week intervals (qw, q2w, q4w) for the first 4 weeks, and administering a maintenance dose comprising at least 1, 2, 3, 4, or 5 subcutaneous doses, wherein the first subcutaneous dose of the maintenance dose is administered to the subject at 1, 2, or 4 week intervals (qw, q2w, q4w) for 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, or 16 weeks starting 4 weeks after the last intravenous dose of the loading dose.

[0032] In one embodiment of any one of the above aspects and embodiments, the anti-IL-36R antibody is administered as a maintenance dose in one or more intravenous or subcutaneous doses beginning on week 4, wherein the total maintenance dose is at least 1200 mg, 1800 mg, 2400 mg, 3000 mg, 3600 mg, 4800 mg, or 6000 mg. In a preferred embodiment, 1, 2, 3, 4 subcutaneous doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, 3000 mg, or any combination thereof are delivered every 1, 2, or 4 weeks (qw, q2w, q4w) on weeks 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0033] In one embodiment of any one of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is at least 1200 mg, 1800 mg, 2400 mg, 3000 mg, 3600 mg, 4800 mg, 6000 mg, 7200 mg, or 8000 mg in the first 4 weeks, followed by 1, 2, 3, 4, 5, or 6 subcutaneous maintenance doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, or a combination thereof, delivered every 1, 2, or 4 weeks (qw, q2w, q4w) in weeks 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In a preferred embodiment, the maintenance dose is delivered as four subcutaneous doses of 300, 450, 600, 900 mg, 1200 mg, delivered every week (qw) from week 4 to week 8 for a total maintenance dose of 1200 mg, 1800 mg, 2400 mg, 3600 mg, or 4800 mg. In another embodiment, the maintenance dose is delivered as two subcutaneous administrations of 2400 mg or 3000 mg, delivered every two weeks from week 4 to week 8 for a total maintenance dose of 4800 mg or 6000 mg. In another embodiment, the maintenance dose is delivered as a single subcutaneous dose of 4800 mg or 6000 mg, delivered from week 4 to week 8 for a total maintenance dose of 4800 mg or 6000 mg.

[0034] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein the total loading dose is 1800 mg (e.g., 450 mg / qw), followed by at least 1, 2, 3, 4, 5, or 6 subcutaneous doses of 300 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0035] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is 3600 mg (e.g., 900 mg / qw), followed by at least 1, 2, 3, 4, 5, or 6 subcutaneous doses of 600 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0036] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is 3600 mg (e.g., 900 mg / qw), followed by at least 1, 2, 3, 4, 5, or 6 subcutaneous doses of 1200 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0037] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is 7200 mg (e.g., 1800 mg / qw), followed by at least 1, 2, 3, 4, 5, or 6 subcutaneous doses of 1200 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0038] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is 6000 mg (e.g., 3000 mg / q2w), followed by at least 1, 2, 3, 4, 5, or 6 subcutaneous doses of 600 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0039] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein a total loading dose is 6000 mg, followed by 1, 2, 3, 4, 5, or 6 subcutaneous doses of 1200 mg administered every two weeks, e.g., at weeks 4, 6, 8, 10, 12, or 14.

[0040] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous or subcutaneous doses, wherein the total loading dose is at least 1200 mg, 1800 mg, 3000 mg, 3600 mg, 7200 mg, or 8000 mg, followed by at least one subcutaneous dose of 300 mg, 600 mg, or 1200 mg administered weekly in weeks 4, 5, 6, and 7. In a non-limiting exemplary embodiment, for a total maintenance dose of 1200 mg, four subcutaneous doses of 300 mg are delivered weekly in weeks 4, 5, 6, and 7, for a total maintenance dose of 2400 mg, four subcutaneous doses of 600 mg are delivered weekly in weeks 4, 5, 6, and 7, or for a total maintenance dose of 3600 mg, four subcutaneous doses of 1200 mg are delivered weekly in weeks 4, 5, 6, and 7. In a related embodiment, at least one maintenance dose is administered after the last dose, including the loading dose.

[0041] Table 2: Exemplary Maintenance Doses Weeks 4-8 [Table 2]

[0042] In one embodiment of any of the above aspects and embodiments, anti-IL-36R antibody maintenance therapy comprising at least one subcutaneous dose can be continued beyond week 8, wherein the subcutaneous dose can remain the same or can be set at increasing or decreasing doses, wherein each dose is 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, administered every two weeks (q2w) or every four weeks (q4w) from week 8 onwards, followed by a final subcutaneous maintenance dose (e.g., for 4-8 weeks). In a non-limiting exemplary embodiment, for a total maintenance dose of 1200 mg, four subcutaneous doses of 300 mg are delivered weekly in weeks 4, 5, 6, and 7, followed by at least one subcutaneous dose of 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, preferably administered every two weeks (q2w), from week 8 through week 52. In another embodiment, for a total maintenance dose of 2400 mg, four subcutaneous doses of 600 mg are delivered weekly in weeks 4, 5, 6, and 7, followed by at least one subcutaneous dose of 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, preferably administered every two weeks (q2w), from week 8 through week 52. In yet another alternative embodiment, for a total maintenance dose of 3600 mg, four subcutaneous doses of 1200 mg are delivered once weekly in weeks 4, 5, 6, and 7, followed by at least one subcutaneous dose of 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg administered preferably every two weeks (q2w) from week 8 through week 52.

[0043] Table 3: Exemplary Maintenance Doses Weeks 8 through 52 [Table 3]

[0044] In another embodiment of any of the first to sixth embodiments or aspects above, the administration results in an efficacy endpoint of: (a) % change from baseline in dT counts at week 12 (b) achievement of hidradenitis suppurativa clinical response (HiSCR) at week 12; (c) Absolute change from baseline in International Hidradenitis Suppurativa Severity Scoring System (IHS4) scores at week 12 (d) Absolute change from baseline in Hidradenitis Suppurativa Area Severity Index (HASI) score at week 12 (e) Achieving at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at Week 12. (f) Achievement of a Physician Global Assessment (PGA) score of 0 or 1 at Week 12 (g) Occurrence of complete disappearance of dT at 12 weeks (h) occurrence of at least one flare (defined as at least a 25% increase in the number of ANs with a maximum increase of two over baseline by week 12); (i) Absolute change from baseline in Dermatology Life Quality Index (DLQI) score at week 12 (j) Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at week 12 One or more of the following will result:

[0045] In another embodiment of any of the first to sixth embodiments or aspects above, the administration results in an efficacy endpoint of: (a) % change from baseline in dT counts at week 8 and / or week 16; (b) absolute change from baseline in IHS4 values ​​at week 8 and / or week 16; (c) absolute change from baseline in Hidradenitis Suppurativa Area-Severity Index (HASI) score at week 16; (d) achievement of hidradenitis suppurativa clinical response (HiSCR50) at week 16; (e) % change from baseline in abscess count at week 16; (f) achievement of at least a 50% reduction in dT counts relative to baseline at week 16; (g) achieving at least a 50% reduction in abscess counts and dT (AdT) counts compared to baseline at week 16; (h) achievement of at least a 50% reduction in ANdT counts relative to baseline at week 16; (i) achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at week 16; (j) % change from baseline in dT counts at each scheduled assessment time point; (k) achievement of at least a 50% reduction from baseline in dT counts at each scheduled assessment time point; (l) occurrence of complete disappearance of dT at each scheduled evaluation time point; (m) time to first occurrence of complete disappearance of dT during treatment; (n) % change from baseline in abscess counts at each scheduled assessment time point; (o) achievement of at least a 50% reduction from baseline in abscess counts at each scheduled evaluation time point; (p) occurrence of complete resolution of the abscess at each scheduled evaluation time point; (q) % change from baseline in total AdT counts at each scheduled assessment time point; (r) achievement of at least a 50% reduction from baseline in AdT counts at each scheduled assessment time point; (s) % change from baseline in inflammatory nodule (N) count at each scheduled assessment time point; (t) achievement of at least a 30% reduction from baseline in the patient global assessment numerical rating scale for HS pain (NRS30) at each scheduled assessment time point; (u) absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at each scheduled assessment time point; (v) absolute change from baseline in FACIT fatigue scale score at each scheduled assessment time point; (w) absolute change from baseline in Dermatology Life Quality Index (DLQI) score at each scheduled assessment time point; (x) absolute change from baseline in Patient Global Impression of Change (PGI-C) score over time; (y) absolute change from baseline in Patient Global Impression of Severity (PGI-S) score over time; (z) Change from baseline in the Hidradenitis Suppurativa Odor and Drainage Scale (HODS) at each scheduled assessment time point (aa) Change from baseline in NRS pruritus at each scheduled assessment time point; (bb) change from baseline in the Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment time point; (cc) % change from baseline in total ANdT counts at each scheduled assessment time point or (dd) Achieving at least a 50% reduction from baseline in ANdT counts at each scheduled evaluation time point One or more of the following will result:

[0046] In another embodiment of any of the first to sixth embodiments or aspects above, the proportion of individuals having a response to administration is statistically significantly higher for one or more of endpoints (a)-(j) and / or (a)-(dd) compared to individuals to a placebo.

[0047] In a seventh aspect, the present invention relates to a method for treating or preventing recurrence of HS symptoms in a patient who has been treated with one or more parenteral doses of an anti-IL-36R antibody of any of the previous aspects or embodiments, the method comprising administering to the patient a therapeutically or prophylactically effective amount of an anti-IL-36R antibody in one or more intravenous or subcutaneous doses.

[0048] In an eighth aspect, the invention relates to a method of achieving a Hidradenitis Suppurativa Clinical Response (HiSCR50) score in a patient who has been treated with one or more parenteral doses of an anti-IL-36R antibody of any of the previous aspects or embodiments, the method comprising administering to the patient an effective amount of the anti-IL-36R antibody in one or more intravenous or subcutaneous doses.

[0049] In a ninth aspect, the invention relates to a method of achieving complete resolution of HS symptoms in a patient who has been treated with one or more parenteral doses of an anti-IL-36R antibody of any of the previous aspects or embodiments, comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous or subcutaneous doses, wherein the HS symptoms comprise inflammatory lesions, abscesses, draining sinuses / fistulas or draining tracts (dT), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection and / or HS-associated pain.

[0050] In a tenth embodiment, the present invention provides a method of treating hidradenitis suppurativa, including methods of improving the symptoms of HS disease, alleviating the symptoms of HS disease, and improving quality of life for individuals with hidradenitis suppurativa, comprising administering a therapeutically or prophylactically effective amount of an anti-IL-36R antibody of any of the preceding aspects or embodiments, comprising administering to the patient one or more intravenous or subcutaneous doses.

[0051] In an eleventh embodiment, the present invention provides methods for treating specific subpopulations of individuals, including those who have had a subtherapeutic response to prior therapy, including, for example, those who have had an inadequate response to or intolerance to oral antibiotics or those who have contraindications to oral antibiotics. In certain embodiments, the present invention is used to treat HS in subjects who have had an inadequate response to or intolerance to oral antibiotics for the treatment of hidradenitis suppurativa or in subjects who have had an inadequate response to or intolerance to TNF-α inhibitors or those who have contraindications to TNF-α inhibitors. In certain embodiments, the present invention is used to treat HS in subjects who have had an inadequate response to or intolerance to TNF-α for the treatment of hidradenitis suppurativa.

[0052] In a twelfth embodiment, the invention includes treating individuals with an AN count of 1 or more at baseline, 2 or more at baseline, 3 or more at baseline, 4 or more at baseline, or 5 or more at baseline.

[0053] In another embodiment related to the tenth to twelfth embodiments or aspects above, the invention provides a method for reducing inflammatory lesion counts (AN counts) or achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) in an individual with HS, comprising systemically administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, such that AN counts are reduced. Clinical response according to the HiSCR scoring system is defined as at least a 50% reduction from baseline in total AN counts, without an increase in the number of abscesses or draining fistulas.

[0054] In another embodiment of any of the ninth to twelfth embodiments or aspects above, the subject does not have an increase in the number of abscesses and / or an increase in draining fistulas or ducts (dT) after being treated with the anti-IL-36R antibody or antigen-binding portion thereof.

[0055] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for reducing the severity of HS according to the International Hidradenitis Suppurativa Severity Scoring System (IHS4) score, which is the absolute change from baseline according to the IHS4 score for assessing the severity of HS. Determining the IHS4 requires counting nodules, abscesses, and draining tracts / fistulas. The absolute change from baseline or "IHS4" score assesses the severity of HS, and the resulting IHS4 score is calculated as follows: nodules (1x) + abscesses (2x) + draining tracts (4x). A total score of 3 or less indicates mild disease, 4-10 indicates moderate disease, and 11 or greater indicates severe disease.

[0056] In another embodiment of the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving (or alleviating) HS symptoms in a subject with hidradenitis suppurativa, as measured by the severity of HS symptoms according to the Hidradenitis Suppurativa Area-Severity Index (HASI) score, from a high score (e.g., a HASI score of 3 or higher in one or more areas) to a score with no effect or a score with minimal effect (e.g., a HS-PGA score of 0-2), the method comprising administering to the subject an IL-36R inhibitor, e.g., a human IL-36R antibody or an antigen-binding portion thereof, such that the HASI score improves from a high score to a score with no effect or a score with minimal effect. The HASI score is modeled after the Psoriasis Activity-Severity Index (PASI). It includes the four classic signs of HS-associated inflammation: erythema, induration, open ulcers, and drainage canals. Each HASI variable is scored using a Likert score (0-3) for a given body area. For BSA assessment, the number of palms (each palm representing 1% of the patient's BSA) involved in each body region (head, right axilla, left axilla, anterior chest, back, anterior buttocks, posterior buttocks, etc.) was assessed and converted to a percentage of that region. An area score was assigned to each region using the PASI approach (0 = none, 1 = 1-9%, 2 = 10-29%, 3 = 30-49%, 4 = 50-69%, 5 = 70-89%, 6 = 90-100%). To calculate the regional HASI score, the sum of the four clinical variable scores was multiplied by the area score for each involved region. This value was then multiplied by the percentage of BSA for that region to give the regional HASI score. The regional HASI scores were added together to give a cumulative total HASI score (range 0-72). The "HASI" combines assessments of lesion severity and area affected into a single score ranging from 0 (no disease) to 72 (severe disease).

[0057] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving (i.e., lowering) a Hidradenitis Suppurativa Physician's Global Assessment (HS-PGA) score. The present invention also provides a method for lowering the HS PGA score of a subject with hidradenitis suppurativa by at least about two stages, comprising administering an IL-36R inhibitor, e.g., a human IL-36R antibody or an antigen-binding portion thereof. The HS-PGA document is a physician's assessment of the patient's HS at a given time point. The HS-PGA scores a patient's disease severity as clear, minimal, mild, moderate to severe, or very severe based on the presence of abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules (Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846-855). The "HS-PGA score" ranges from 0 to 5. In this case, the scale is 0 (clear: no abscesses, drainage channels, inflammatory nodules, or non-inflammatory nodules), 1 (minimal: no abscesses, drainage channels, or inflammatory nodules and non-inflammatory nodules present), 2 (mild: no abscesses or drainage channels and 1-4 inflammatory nodules, or 1 abscess or drainage channel and no inflammatory nodules), 3 (moderate: no abscesses or drainage channels and 5 or more inflammatory nodules, or 1 abscess or drainage channel and 1 or more inflammatory nodules, or 2-5 abscesses or drainage channels and less than 10 inflammatory nodules), 4 (severe: 2-5 abscesses or drainage channels and 10 or more inflammatory nodules), and 5 (very severe: 6 or more abscesses or drainage channels present).

[0058] In another embodiment related to the above tenth to twelfth embodiments or aspects, the present invention provides a method for reducing the HS-PGA score of a subject with hidradenitis suppurativa from a high score (e.g., a score of 3 or higher) to a score that is not affected or that only slightly affected (e.g., a score of 0 to 2), the method comprising administering a human IL-36R antibody to the subject such that the HS-PGA score is reduced from a high score to a score that is not affected or that only slightly affected.

[0059] In another embodiment related to the above tenth to twelfth embodiments or aspects, the present invention provides a method for reducing the HS-PGA score of a subject with hidradenitis suppurativa by at least about two stages, the method comprising administering a human IL-36R antibody to the subject so that the HS-PGA score is reduced by at least about two stages.

[0060] In another embodiment of the above tenth to twelfth embodiments or aspects, the patient global assessment numerical rating scale (NRS30) of hidradenitis suppurativa (HS) pain can also be used as an index for measuring the efficacy of an anti-IL-36R antibody or its antigen-binding portion in a patient or patient population with hidradenitis suppurativa. In this case, a statistically significant mean improvement in NRS30 pain score (compared to placebo) of at least 30% in a population of treated individuals indicates that the IL-36R antibody is effective in treating hidradenitis suppurativa. The HS Pain NRS is an endpoint for assessing the severity of HS-related pain in clinical trials for individuals with HS. Responses were given on an 11-point scale ranging from 0 (no HS pain) to 1 (the worst HS pain imaginable). In a related embodiment, the present invention provides a method for determining whether a human IL-36R antibody is effective in treating hidradenitis suppurativa based on improvement in NRS30 pain score.

[0061] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving a Dermatological Quality of Life Index (DLQI) score in a subject with hidradenitis suppurativa from a high score (i.e., impaired quality of life) to a low score (i.e., no or little impact on quality of life), comprising administering a human IL-36R antibody to the subject in a manner that reduces the DLQI score from a high score to a low score. The DLQI is a 10-item patient-administered quality-of-life questionnaire covering six domains, including symptoms and emotions, 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 Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6-10 Jul 1993. Clin Exp Dermatol 1994;19:210-216). The response period for the DLQI is one week. Response categories include "not applicable" (score 0), "not at all" (score 0), "a little" (score 1), "quite a bit" (score 2), and "a great deal" (score 3). Question 7 is a "yes" / "no" question, where "yes" is scored as a 3. The total DLQI score is calculated by summing the scores for each question and ranges from 0 to 30. The higher the score, the more impaired the quality of life.

[0062] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving a Hidradenitis Suppurativa Quality of Life (HiS-QoL) score in a subject with hidradenitis suppurativa from a high score (i.e., quality of life is significantly affected) to a low score (minimal impact on quality of life), comprising administering a human IL-36R antibody to the subject in a manner that reduces the HiS-QoL score from a high score to a low score. The HiS-QoL survey is a 17-item patient-administered assessment tool for measuring HS-specific quality of life in clinical trials. The 17 HiS-QoL items include four symptom items, eight activity adjustment items, and five mental health items. Item scores are summed to generate a total ranging from 0 to 68. A higher score indicates a more severe impact on quality of life.

[0063] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving HS symptoms or reducing the severity of HS-associated itch as scored according to the Numerical Rating Scale for Itch (NRS Itch), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score to a low score. The HS Itch NRS is an endpoint for assessing the severity of HS-associated itch in clinical trials of individuals with HS. The patient's global assessment of HS itch assesses the most severe HS itch. The rating, ranging from 0 (no itch) to 10 (the worst imaginable itch in HS), is a unidimensional measure of itch intensity and can be administered daily with minimal burden to study participants. The response period is 24 hours, and responses are given on an 11-point scale ranging from 0 ("no itch") to 10 ("the worst imaginable itch"). Study participants are asked to rate the intensity of their itch using this scale.

[0064] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for improving HS symptoms or reducing the occurrence of drainage and odor resulting from clinical symptoms of HS according to the Hidradenitis Suppurativa Odor and Drainage Scale (HODS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score to a low score. The HODS is an eight-item scale developed to assess drainage and odor associated with HS in individuals. The HODS covers two domains: drainage (five items) and odor (three items). Response options range from 1 to 5. Higher scores indicate a worse assessment of the outcome for this construct.

[0065] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for reducing and / or ameliorating anxiety and / or depression in an individual with HS according to the Hospital Anxiety and Depression Scale (HADS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline to a low score. The HADS is an assessment tool for screening anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 items each for anxiety symptoms and depressive symptoms, with possible scores ranging from 0 to 21 for each subscale.

[0066] In another embodiment related to the tenth to twelfth embodiments or aspects above, the invention provides a method of improving the impact of HS on a patient's work productivity and / or overall activity according to the Work Productivity and Activity Impairment Index for HS (WPAI-HS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score (high impact) to a low score (low impact). The WPAI-HS is a six-item assessment tool for assessing the impact of hidradenitis suppurativa on the ability to work and perform normal daily activities.

[0067] In another embodiment related to the tenth to twelfth embodiments or aspects above, the present invention provides a method for reducing the impact of HS on a patient's quality of life and / or improving the patient's overall quality of life as assessed by the EuroQol 5 dimension 5-level (EQ-5D-5L), comprising administering a human IL-36R antibody to the subject, wherein the improvement is a change from a high impact score to a low impact score. The descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, severe problem, and extreme problem. The EQ VAS records a patient's self-assessed health on a vertical visual analog scale. In this case, the endpoints are labeled "best imaginable health" and "worst imaginable health."

[0068] In another embodiment of the tenth to twelfth embodiments or aspects above, the proportion of individuals who respond positively to administration of anti-IL-36R is statistically and / or significantly higher for one or more endpoints compared to individuals who respond to a placebo. The endpoint may be a composite score of multiple scores using various assessment tools.

[0069] In a thirteenth aspect, the present invention relates to a method for treating and / or preventing recurrence of HS symptoms in a patient who has been treated with one or more parenteral doses of an anti-IL-36R antibody of any of the above aspects or embodiments, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous or subcutaneous doses.

[0070] In a fourteenth aspect, the present invention relates to a method of achieving a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas in a patient treated with one or more doses of an anti-IL-36R antibody of any of the above aspects or embodiments, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous or subcutaneous doses.

[0071] In a fifteenth aspect, the invention relates to a method of achieving improvement in one or more HS symptoms in a patient treated with one or more intravenous or subcutaneous doses, including a loading dose, followed by one or more subcutaneous doses, including a maintenance dose, of an anti-IL-36R antibody of any of the above aspects or embodiments, wherein the HS symptoms comprise inflammatory lesions, abscesses, draining tracts / fistulas or drainage tracts (dT), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection and / or HS-associated pain.

[0072] In one embodiment of any of the above thirteenth to fifteenth aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show significant clinical improvement as measured by % change from baseline in total AN counts at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0073] In one embodiment of any of the above thirteenth to fifteenth aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show a significant clinical improvement in HS flare incidence (flare incidence defined as at least a 25% increase in AN number accompanied by a minimum increase of two incidences) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0074] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of individuals show significant clinical improvement as measured by change in % change from baseline in total dT counts at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

[0075] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of individuals exhibit complete clearance of dT at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

[0076] In one embodiment of any of the thirteenth through fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals achieve a clinical response as measured by a Hidradenitis Suppurativa Clinical Response Score (HiSCR), defined as at least a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0077] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show significant clinical improvement as measured by absolute change from baseline in the International Hidradenitis Suppurativa Severity Scoring System (IHS4) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0078] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of individuals show significant clinical improvement as measured by absolute change from baseline in the Hidradenitis Suppurativa Area and Severity Index (HASI) at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

[0079] In one embodiment of any of the above thirteenth to fifteenth aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals exhibit a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0080] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals exhibit a score of 0 or 1 as measured by Physician Global Assessment (PGA) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0081] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show clinical improvement as measured by absolute change from baseline in Dermatology Life Quality Index (DLQI) score at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0082] In one embodiment of any of the above thirteenth to fifteenth aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show clinical improvement as measured by absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0083] In one embodiment of any of the thirteenth to fifteenth aspects or related embodiments above, the proportion of individuals having a response to administration is statistically significantly higher for any of the mentioned endpoints compared to individuals to a placebo.

[0084] In another aspect, the invention relates to a method of treating HS in a patient, the method comprising: (a) obtaining a biological sample from the patient, wherein the biological sample is obtained from a source including lesional skin or whole blood; (b) determining a gene expression profile of one or more genes; and (c) administering to the patient an effective amount of an anti-IL-36R antibody of any embodiment related to any of the above aspects.

[0085] In one embodiment of the tenth aspect, the one or more genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24 or IL1B in lesional skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9 or CD177 in whole blood.

[0086] It will also be understood that any of the methods, administration schemes and / or dosing regimens disclosed herein apply equally to the use of the anti-IL-36R antibodies disclosed in such methods, administration schemes and / or dosing regimens, i.e., any of the anti-IL-36R antibodies disclosed herein, for use in the treatment, prevention, alleviation and / or amelioration of any of the disclosed diseases and / or conditions. That is, the present invention also provides the use of an anti-IL-36R antibody disclosed herein for the manufacture of a medicament for the treatment, prevention, alleviation and / or amelioration of any of the disclosed diseases and / or conditions.

[0087] Additional features and advantages of the present invention will become apparent upon review of the ensuing detailed description set forth below, and in part will be obvious from the description, or may be learned by practice of the subject technology. It is to 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. [Brief explanation of the drawings]

[0088] The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate aspects of the subject technology, and together with the description, serve to explain the principles of the invention. [Figure 1] Figure 1 shows the ligands of IL-36 antagonists (IL-36RA / IL1F5, IL-38 / ILF10) that inhibit the signaling cascade. [Figure 2]Figure 2 shows the expression of IL-36 ligands in human skin biopsies by in situ hybridization (ISH). The figure shows formalin-fixed, paraffin-embedded (FFPE) skin biopsies from HS lesional and non-lesional HS samples that were purchased from a vendor and stained for IL-36α, β, and γ using ISH probes. Increased expression of all three IL-36 ligands, α, β, and γ, was confirmed in HS skin samples. [Figure 3] Figures 3A-3B. A. Phase IIa Clinical Trial Design: A clinical proof-of-concept study designed to explore the efficacy of spesolimab in individuals with moderate to severe HS. Eligible individuals also had HS lesions in two or more different body regions, a total number of abscesses and inflammatory nodules (AN) of 5 or more, a total number of drainage tracts of 20 or less, were biologic-naïve or had failed prior TNFi treatment for HS, and had an inadequate response to oral antibiotics for HS in the past year. †HS disease worsening was defined as a 150% increase in AN counts from baseline. Monotherapy rescue therapy with 100 mg doxycycline orally twice daily or alternative therapy at the investigator's discretion was allowed for up to two weeks, for a total of four weeks during the study. 3B. Baseline Patient Demographics: ‡HS severity was based on the IHS4 criteria. AN, abscesses and inflammatory nodules; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Severity Score System; iv, intravenous; OLE, open-label extension study; qw, once weekly; q2w, once every 2 weeks; SC, subcutaneous; SD, standard deviation; TNFi, TNF inhibitor. [Figure 4] Figure 4. Flowchart of Phase IIa trial activities. [Figure 5]Figures 5A-5B. A. LS mean % change from baseline in total abscess and inflammatory nodule (AN) counts: LS means, differences, and confidence intervals were estimated using a MMRM-based (REML) method, including categorical fixed effects of treatment at each visit, continuous effects of stratum already using TNF inhibitors and baseline at each visit, and a random effect of subject. Analyses use data up to salvage therapy use, and censor data after salvage therapy use. Results are presented narratively, and individuals with no missing values ​​are included in the summary. B. Mean absolute change from baseline in lesion counts at week 12: All types of HS inflammatory lesion counts showed a trend toward a decrease after treatment with spesolimab. AN, abscess and inflammatory nodule; dT, drainage duct; LS, least squares; SD, standard deviation; SE, standard error. [Figure 6] Figures 6A-6B. A. Percent change from baseline in dT counts at week 12. A greater proportion of individuals in the spesolimab group showed a decrease from baseline in dT counts at week 12 compared with the placebo group. 66.7% (16 / 24) of individuals in the spesolimab group showed a decrease from baseline in dT counts at week 12 compared with 38.5% (5 / 13) of individuals in the placebo group. B. LS mean % change from baseline in dT counts: LS means, differences, and confidence intervals were estimated using a MMRM-based (REML) method, including categorical fixed effects of treatment at each visit, continuous effects of stratum already using TNF inhibitors and baseline at each visit, and a random effect of subject. Data up to the use of rescue therapy were used for the analysis, and data after the use of rescue therapy were censored. dT, drainage; LS, least squares; SE, standard error. [Figure 7] Figure 7. Safety profile of spesolimab: The safety profile was similar to previous trials. No serious adverse events were observed in patients receiving spesolimab. At week 2, two individuals experienced treatment reversal, leaving 36 individuals receiving spesolimab. †Serious AEs were defined as RCTC grade 3 or 4. ‡Per ICH E3 guidelines. AE, adverse event; AESI, adverse event of special interest; AN, abscess and inflammatory nodule; HS, hidradenitis suppurativa; N, nodule; RCTC, rheumatology common toxicity criteria. [Figure 8] Figures 8A-8B. A. Phase IIa and OLE study design: †At week 24 (week 12 of OLE), individuals could increase their spesolimab dose to 1200 mg SC q2w if needed (based on responder status at OLE initiation and change in HS-PGA severity from OLE initiation). ‡HS disease worsening was defined as a 150% increase from baseline in abscess and inflammatory nodule counts. Systemic antibiotic or immunosuppressive biologic monotherapy was not included. §Baseline refers to the last measurement before spesolimab initiation, i.e., baseline of the prior spesolimab Phase IIa study or baseline of the prior placebo OLE study (IV, intravenous; OLE, open-label extension; q2w, once every 2 weeks; R, randomization; SC, subcutaneous; SD, standard deviation). B. OLE Patient Characteristics at Baseline: Individuals eligible for inclusion criteria had HS lesions in two or more different body regions, a total number of abscesses and inflammatory nodules (AN) of 5 or more, a total number of drainage ducts of 20 or less, were biologic-naive or had failed previous TNFi treatment for HS, and had an inadequate response to oral antibiotics for HS in the past year (DLQI, Dermatology Quality of Life Index; HASI, Hidradenitis Suppurativa Area-Severity Index; HiS-QOL, Hidradenitis Suppurativa Quality of Life; HS, Hidradenitis Suppurativa; HS-PGA, Hidradenitis Suppurativa Physician Global Assessment; IHS4, International Hidradenitis Suppurativa Severity Scoring System). [Figure 9]Figures 9A-9D. Absolute change from baseline to week 50 for lesion type and IHS4 score: 95% CI calculated based on Student's t-distribution. At baseline, the number of patients was n = 30 for previous spesolimab and n = 15 for previous placebo. For change from baseline, only individuals with one or more relevant lesion types were included. At week 50, the number of patients was n = 15 for previous spesolimab and n = 7 for previous placebo (excluding all assessments after rescue medication). CI, confidence interval; IHS4, International Hidradenitis Suppurativa Severity Scoring System). A. Mean absolute change from baseline (95% CI) in drainage tract count. Previous spesolimab group = -1.3 (-2.9, 0.3); previous placebo group = -3.7 (0.3, -7.8) (only individuals with one or more drainage tracts at baseline were included). B. Mean absolute change from baseline (95% CI) in inflammatory nodule count. Previous spesolimab group = -3.7 (-7.9, 0.5); Previous placebo group = -5.7 (-8.7, -2.8) (only individuals with one or more inflammatory nodules at baseline were included). C. Mean absolute change from baseline (95% CI) in abscess count. Previous spesolimab group = -0.9 (-2.2, 0.5); Previous placebo group = -2.4 (-7.6, 2.8) (only individuals with one or more abscesses at baseline were included). D. Mean absolute change from baseline (95% CI) in IHS4 score. Previous spesolimab group = -12.8 (-20.7, -5.0); Previous placebo group = -23.4 (-50.8, 4.0). [Figure 10] Figures 10A-10B. A. Part 1 (Phase IIb) study design. A multicenter, double-blind, placebo-controlled, randomized study evaluating the efficacy and safety of spesolimab compared to placebo in individuals with moderate to severe HS. B. Part 2 (Phase III) study design: This study will begin after the primary analysis of Part 1 (Phase IIb) to evaluate further development benefits and interactions with HS. Part 2 was approved by the IRB / EC. (IC = informed consent, V = study visit, W = weeks (study week), FUP = follow-up, EoT = end of treatment, EoS = end of study, REP = residual effect period). [Figure 11]Figures 11A and 11B. Flowchart of Phase IIb clinical trial activities. A. Treatment period up to week 32. B. Treatment period from week 32 onwards to week 48.

[0089] Detailed Description of the Invention Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. The scope of the present invention will be limited only by the appended claims.

[0090] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the subject technology can be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail in order to avoid obscuring the present invention.

[0091] 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 belongs.

[0092] The inventors have surprisingly found that the interleukin-36 pathway is inhibited in HS individuals treated with a high loading dose of an anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the present invention. As a result, positive primary indicators of response included percent change from baseline in dT counts, absolute change from baseline in IHS4 (dT, abscess, and inflammation weighted counts), absolute change from baseline in HASI (HS Severity Index), and other clinical symptoms in individuals at 12 weeks of treatment.

[0093] In one aspect, the present invention relates to a method for treating, preventing, or ameliorating hidradenitis suppurativa (HS) in a subject, comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody (disclosed herein) or antigen-binding fragment thereof, hi an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0094] While not wishing to be bound by this theory, it is believed that anti-IL-36R antibodies or antigen-binding fragments thereof bind to human IL-36R, thereby preventing the binding of IL-36 agonists and, as a result, at least partially blocking the signaling cascade from IL-36R to inflammatory mediators involved in hidradenitis suppurativa (HS). IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been reported that agonistic IL-36 ligands (α, β, or γ) bind to the IL-36 receptor and then initiate the signaling cascade by forming a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP).

[0095] IL36R is a cell surface receptor involved in inflammatory responses in the skin and intestine. It is a novel member of the IL1R family that forms heterodimeric complexes with IL1R accessory proteins. The heterodimeric IL36R system, which has stimulatory (IL36α, IL36β, IL36γ) and inhibitory (IL36Ra) ligands, shares many 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) signal through a unique cognate receptor protein that, upon ligand binding, recruits the common IL1RacP subunit and activates NFkB and MAP kinase pathways in receptor-positive cell types. In human skin tissue, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrating myeloid cells. Activation of IL36R in skin tissue promotes the production of inflammatory mediators (e.g., CCL20, MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and modulates the expression of tissue remodeling genes (e.g., MMPs, TGF-β).

[0096] The anti-IL36R antibodies of the invention herein are disclosed, for example, in US Pat. No. 9,023,995, the entire contents of which are incorporated herein by reference.

[0097] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0098] definition The use of a phrase such as "aspect" does not imply that such aspect is essential to the invention or that such aspect applies to all configurations of the subject technology. The disclosure of an aspect may apply to all configurations or one or more configurations. An aspect may provide one or more examples of the disclosure. A phrase such as "aspect" may refer to one or more aspects, and vice versa. The use of a phrase such as "embodiment" does not imply that such embodiment is essential to the subject technology or that such embodiment applies to all configurations of the subject technology. The disclosure of an embodiment may apply to all embodiments or one or more embodiments. An embodiment may provide one or more examples of the disclosure.

[0099] The term "about" generally refers to an acceptable error or range of variation for a measurement given the nature or precision of the measurement. Typical and illustrative error or range of variation is 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 ​​therebetween (e.g., in the range of 95-105, 95.1, 95.2, etc.; in the range of 97-103, 97.1, 97.2, etc.; in the range of 99-101, 99.1, 99.2, etc.). Numerical values ​​given herein are approximate unless otherwise specified, meaning that this can be inferred even when the term "about" is not explicitly stated.

[0100] Therapeutic Uses of Antibodies The role of neutrophils in skin inflammation is increasingly understood. Although the genetically based role of the IL-36 pathway and its proven inhibition by spesolimab are clear, the involvement of the same pathway in other similar neutrophilic skin diseases (NDs) is being recognized. NDs are a heterogeneous group of diseases with common characteristics and overlapping pathophysiological features. This disease is primarily associated with skin symptoms due to neutrophil accumulation, but additional tissue involvement has also been observed. Our research suggests that the IL-36 pathway plays an important role in the progression of disease symptoms in pustular neutrophilic skin diseases (NDs), such as hidradenitis suppurativa (HS). Therefore, blocking the IL-36 pathway may be beneficial for skin inflammation accompanied by papules, nodules, and plaques, such as hidradenitis suppurativa (HS).

[0101] The present invention provides anti-IL-36R antibodies and pharmaceutical compositions comprising anti-IL-36R antibodies for use in lowering, reducing or blocking the IL-36 pathway, useful for treating or preventing hidradenitis suppurativa (HS) in a subject, preferably a human.

[0102] In one embodiment, the present invention provides a pharmaceutical composition formulated in a unit dosage form, wherein such unit dosage form contains at least 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of the anti-IL-36R antibody. In a related embodiment, the unit dosage form is used in the manufacture of a medicament for treating a subject with hidradenitis suppurativa (HS). In a related embodiment, the unit dosage form is a parenteral (e.g., intravenous or subcutaneous) dosage form.

[0103] In a related embodiment, the invention provides pharmaceutical preparations (or "articles of manufacture" as described below). The pharmaceutical preparation comprises one, two, three or four of the unit dosage forms comprising 300 mg of the anti-IL-36R antibody; one, two, three or four of the unit dosage forms comprising 450 mg of the anti-IL-36R antibody, or one, two, three or four of the unit dosage forms comprising 600 mg of the anti-IL-36R antibody, or one, two, three or four of the unit dosage forms comprising 900 mg of the anti-IL-36R antibody, or one, two, three or four of the unit dosage forms comprising 1200 mg of the anti-IL-36R antibody, or one, two, three or four of the unit dosage forms comprising 1800 mg of the anti-IL-36R antibody, or one, two, three or four of the unit dosage forms comprising 2000 mg of the anti-IL-36R antibody, or one or two of the unit dosage forms comprising 2400 mg of the anti-IL-36R antibody, or one or two of the unit dosage forms comprising 3000 mg of the anti-IL-36R antibody, or any combination thereof to achieve an effective dose.

[0104] In a related embodiment, one, two, three, or four of the unit dosage forms (e.g., in a pharmaceutical preparation) are administered at intervals of one week (qw), two weeks (q2w), or four weeks (q4w). Preferably, when the unit dosage form contains 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, or 2000 mg of the anti-IL-36R antibody, one, two, three, or four unit dosage forms are administered at intervals of one week (qw), two weeks (q2w), or four weeks (q4w). When the unit dosage form contains 2400 mg or 3000 mg of the anti-IL-36R antibody, one or two unit dosage forms are administered at intervals of two weeks (q2w) or four weeks (q4w). When the unit dosage form contains 300 mg of the anti-IL-36R antibody, 1, 2, 3 or 4 unit dosage forms are administered as subcutaneous maintenance doses at intervals of 1 (qw) or 2 weeks (q2w).

[0105] In one aspect, the present invention relates to a method for treating, preventing, or ameliorating hidradenitis suppurativa (HS) in a subject, comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody (disclosed herein) or antigen-binding fragment thereof, hi an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0106] In one aspect, the invention relates to the use of an anti-IL-36R antibody (as disclosed herein) or an antigen-binding fragment thereof in the manufacture of a medicament for treating, preventing, or ameliorating hidradenitis suppurativa (HS). In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0107] Preferably, the HS is moderate to severe. "Moderate to severe HS" can be determined based on the criteria of the International Hidradenitis Severity Rating System (IHS4), determined by the investigator by interviewing the participant and / or reviewing their medical history for at least one year prior to the baseline visit. If IHS4 scoring is unavailable, an equivalent scoring system, such as the HS-PGA or Hurley, is acceptable based on the investigator's documented assessment. More preferably, the HS lesions are present in at least two different anatomical regions (e.g., right / left axilla, groin, inframammary area, perineum). More preferably, the HS is biologic-naïve and has failed prior treatment with a TNF inhibitor (TNFi) for HS. More preferably, if the HS is biologic-naïve, an inadequate response to an appropriate course of oral antibiotics appropriate for HS treatment has occurred within the past year, at the investigator's discretion.

[0108] In one aspect, the present invention relates to a method of treating a skin disorder associated with hidradenitis suppurativa (HS) in a patient, comprising administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the invention (as disclosed herein). In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0109] In one aspect, the present invention relates to a method of treating skin inflammation associated with hidradenitis suppurativa (HS) in a subject, comprising administering to the subject or having administered to the subject a therapeutically effective amount of an anti-IL-36R antibody of the invention (as disclosed herein) or an antigen-binding fragment thereof. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0110] In one aspect, the present invention relates to a method for preventing or reducing neutrophil infiltration in affected skin tissue of a subject suffering from hidradenitis suppurativa (HS), comprising administering to the subject or having administered to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0111] An infectious process in HS has long been suspected (Highet AS, Warren RE, Staughton RC, Roberts SO. Streptococcus milleri causing treatable infection in perineal hidradenitis suppurativa. Br J Dermatol. 1980;103:375-82). For example, one study found that anaerobic bacteria, such as Prevotella and Porphyromonas, coagulase-negative Staphylococcus, and Staphylococcus aureus were commonly identified in HS lesions (Wark KJL, Cains GD. The Microbiome in Hidradenitis Suppurativa: A Review. Dermatol Ther (Heidelb). 2021 Feb;11(1):39-52).

[0112] The microbiome within the drainage tract of individuals with hidradenitis suppurativa was also investigated, and overall, five microbiome types were identified: Porphyromonas species (Type I), Corynebacterium species (Type II), Staphylococcus species (Type III), Prevotella species (Type IV), and Acinetobacter species (Type V). Porphyromonas species (Type I) and Prevotella species (Type IV) were the most frequently found genera within the drainage tract (Ring HC, et al. The Follicular Skin Microbiome in Individuals With Hidradenitis Suppurativa and Healthy Controls. JAMA Dermatol. 2017 Sep 1;153(9):897-905).

[0113] In one study, bacterial cultures detected anaerobic bacteria in 83% of HS lesions and 53% of control samples. Additionally, milleri group streptococci and actinomycetes were detected in 33% and 26% of cases, respectively. High-throughput sequencing identified 43 taxa associated with HS lesions. Two gram-negative anaerobic bacillus taxa, Prevotella and Porphyromonas, were dominant, in contrast to the paucity of aerobic commensals. Rare taxa in the normal subcutaneous fat microbiota were associated with lesions independently of sex, duration and family history of HS, body mass index, and site. Two additional major taxa, Fusobacterium and Parvimonas, correlated with the clinical severity of HS (Guet-Revillet H, Jais JP, Ungeheuer MN, Coignard-Biehler H, Duchatelet S, Delage M, Lam T, Hovnanian A, Lortholary O, Nassif X, Nassif A, Join-Lambert O. The Microbiological Landscape of Anaerobic Infections in Hidradenitis Suppurativa: A Prospective Metagenomic Study. Clin Infect Dis. 2017 Jul 15;65(2):282-291).

[0114] In Guet-Revillet, et al., 2014, researchers correlated the severity of HS disease with two different microbiological profiles related to the clinical staging of the lesions according to the Hurley scale (Guet-Revillet, H., Coignard-Biehler, H., Jais, J., Quesne, G., Frapy, E., Poiree, S., et al.(2014). Bacterial Pathogens Associated with Hidradenitis Suppurativa, France. Emerging Infectious Diseases, 20(12), 1990-1998). Although there is no consensus on a severity classification system, the Hurley staging system is the most commonly used (Hurley HJ. Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach. In: Roenigk RK, Roenigk HH Jr, eds. Roenigk and Roenigk's Dermatologic Surgery: Principles and Practice. 2nd ed. New York, NY: Marcel Dekker; 1996:623-645). Very briefly, the Hurley system classifies HS into three stages: Stage 1: one or more abscesses without fistula formation or scarring (most common); Stage 2: recurrent abscesses with one or more fistulas widely separated by intact skin and scarring; and Stage 3: multiple, extensively intervening fistulas not separated by intact skin.

[0115] In Guet-Revillet et al. (2014), researchers demonstrated that two specific microbiological profiles, which correspond neither to normal skin microbiota nor to common skin pathogens (S. aureus and S. pyogenes), are associated with HS lesions and disease severity. The first microbiological profile, "Profile A," was characterized primarily by pure or predominant cultures of S. lugdunensis, associated with Hurley stage 1 lesions (low severity scores). The second microbiological profile, "Profile B," was a mixed flora composed of Gram-negative and Gram-positive strict anaerobes, anaerobic actinomycetes, and milleri group streptococci. Various other bacteria, such as S. aureus, coagulase-negative staphylococci, corynebacteria, Enterobacteriaceae, Propionibacterium species, and Enterococcus species, were irregularly and in low abundance with the mixed anaerobic flora, especially when lesions were sampled by swabbing. This profile was primarily observed in Hurley stages 2 and 3 and was associated with open abscess lesions, which were also observed in 24% of Hurley stage 1 lesions.

[0116] In one aspect, the present invention relates to a method for reducing microbial colonization in the skin of a subject with hidradenitis suppurativa (HS), comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof disclosed herein. In an embodiment of this aspect, the colonization is by a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, molluscum contagiosum virus, herpes simplex virus, coxsackievirus, vaccinia virus, Candida albicans, Microsporum species, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment of this aspect, the microorganism is Staphylococcus aureus (S. aureus). In another embodiment related to this aspect, S. aureus colonization is reduced by at least 10% or at least 20% from baseline after administration of an anti-IL-36R antibody or antigen-binding fragment thereof disclosed herein. In an embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0117] In one aspect, the invention relates to a method of reducing susceptibility to skin infection in a subject with hidradenitis suppurativa (HS), comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof disclosed herein (as disclosed herein). In an embodiment of this aspect, the skin infection is caused by a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, herpes simplex virus, molluscum contagiosum virus, coxsackievirus, vaccinia virus, Candida albicans, Microsporum species, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment of this aspect, the microorganism is Staphylococcus aureus (S. aureus). In an embodiment of this aspect, the anti-IL-36R antibody is spesolimab.

[0118] In embodiments of any of the above aspects, a second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody or antigen-binding fragment thereof. In related embodiments, the second therapeutic agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antifungal agent, another IL-36R antagonist, an IgE inhibitor, a corticosteroid, an NSAID, an IL-4R antagonist, and IFNγ.

[0119] In embodiments of any of the above aspects, 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 or 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).

[0120] In embodiments of any one of the above aspects, 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: 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).

[0121] In an embodiment of any of the above aspects, the anti-IL-36R antibody is 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); and 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); or 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); and 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); or 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); and 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); or iv. 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: 105 (L-CDR2); and 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); or va) 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); and 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); or vi. 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: 140 (L-CDR2); and 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); or vii.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); and 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: 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). Includes:

[0122] In an embodiment of any one of the above aspects, 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. 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 Includes:

[0123] In an embodiment of any of the above aspects, the anti-IL-36R antibody is i. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or iv. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125, or v. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126, or vi. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or vii. a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or viii. A light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139, or ix. A light chain comprising the amino acid sequence of SEQ ID NO: 124 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 Includes:

[0124] In another embodiment of any of the above aspects or embodiments described herein, the anti-IL-36R antibody is spesolimab.

[0125] In another embodiment of any of the above aspects or embodiments described herein, a second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody.

[0126] In another embodiment of any of the above aspects or embodiments described herein, the second therapeutic agent is selected from the group consisting of an antibacterial agent, an antiviral agent, an antifungal agent, an anti-IL-36R antibody, an IgE inhibitor, a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), an IL-4R antagonist, and IFNγ.

[0127] Pharmaceutical Composition The antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for administration to a subject. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers, diluents, and / or excipients, in single or multiple doses. Pharmaceutical compositions for administration are designed to suit the selected administration method, and pharmaceutically acceptable diluents, carriers, and / or excipients, such as dispersants, buffers, surfactants, preservatives, solubilizers, isotonicity agents, stabilizers, etc., are used as needed. The compositions can be designed according to conventional techniques, e.g., Remington, The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA 1995, which provides practitioners with an overview of commonly known formulation techniques.

[0128] Pharmaceutical compositions comprising the anti-IL-36R monoclonal antibodies of the present invention can be administered to a subject suffering from a neutrophilic skin disease described herein using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0129] The route of administration of the antibody of the present invention can be oral, parenteral, inhalation, or topical. Preferably, the antibody of the present invention can be incorporated into a pharmaceutical composition suitable for parenteral administration. As used herein, the term parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal, or intraperitoneal administration. Peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection or infusion is preferred. Vehicles suitable for such injections are known in the art.

[0130] Such pharmaceutical compositions must typically be sterile and stable under the conditions of manufacture and storage in the containers provided (e.g., sealed vials or syringes (e.g., holding unit dosage forms)). Thus, pharmaceutical compositions may be sterile filtered after formulation or may be rendered microbiologically acceptable in some manner. A typical composition for intravenous infusion may have a volume of approximately 250-1000 ml of a liquid, such as sterile Ringer's solution, saline, dextrose solution, or Hank's solution, and an antibody concentration at a therapeutically effective dose (e.g., 1-100 mg / mL or higher). Dosages may vary depending on the type and severity of the disease. As is well known in the medical field, the dosage for any given subject depends on many factors, including the patient's size, body surface area, age, the particular compound being administered, sex, time and route of administration, health status, and other drugs being administered concomitantly. A typical dosage may range, for example, from 0.001 to 1000 mg. However, dosages below or above this exemplary range are contemplated, particularly considering the aforementioned factors.

[0131] As used herein, the term "dose" refers to the amount of an anti-IL-36R antibody, or antigen-binding portion thereof, administered to a subject.

[0132] As used herein, the term "administration" refers to administering an anti-IL-36R antibody, or an antigen-binding portion thereof, to achieve a therapeutic objective (e.g., treatment of hidradenitis suppurativa).

[0133] "Dosing regimen" refers to a treatment schedule of an anti-IL-36R antibody or antigen-binding portion thereof, e.g., a chronic treatment schedule or a treatment schedule over the entire course of treatment, e.g., a first dose of an anti-IL-36R antibody or antigen-binding portion thereof is administered at week 0, followed by a second, third, and / or fourth dose of an anti-IL-36R antibody or antigen-binding portion thereof in a weekly or biweekly dosing regimen.

[0134] The term "multiple-variable doses" includes different doses of an anti-IL-36R antibody or antigen-binding portion thereof administered to a subject for therapeutic treatment. A "multiple-variable dose regimen" or "multiple-variable dose therapy" refers to a treatment schedule based on administering different amounts of an anti-IL-36R antibody or antigen-binding portion thereof at different time points throughout the course of treatment.

[0135] As used herein, the terms "intravenous dose" (iv) and "subcutaneous dose" (sc) refer to the route of administration of an anti-IL-36R antibody. A "loading dose" may be an intravenous or subcutaneous dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"), and a loading dose may also be referred to as an "initial dose" or "inducing dose." A "maintenance dose" is typically a subcutaneous dose administered after a loading dose and / or a baseline dose, and a maintenance dose may also be referred to as a "subsequent dose." The loading and maintenance intravenous and subcutaneous doses may all contain the same amount of anti-IL-36R antibody or antigen-binding fragment thereof, but may generally differ from each other in terms of the amount of antibody administered or the frequency of administration. In embodiments, the loading dose is equal to or greater than the maintenance dose. A "loading dose" may be interchangeably referred to as an "initial dose" or "inducing dose" and may be a single dose or, alternatively, a set of doses including a "total loading dose." The maintenance dose may also be referred to as a "subsequent dose" and may be a single dose or, alternatively, a set of doses for administration.

[0136] In certain embodiments, the amounts of anti-IL-36R antibody included in the inducement / initial / loading dose and the maintenance / subsequent dose differ from each other during the treatment period. In certain embodiments, one or more inducement / inducement doses each comprise a first amount of the antibody or antigen-binding fragment thereof, and one or more maintenance / subsequent doses each comprise a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first total loading amount of the antibody or antigen-binding fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the second or subsequent amount of the antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, 5 or more) initial doses are administered at the start of the treatment regimen as "inducement doses" or "loading doses," followed by subsequent doses as "maintenance doses" or "treatment doses." In one embodiment, the total loading dose or total induction dose comprises 1800 mg, 2400 mg, 3600 mg, 4800 mg, 6000 mg, 7200 mg, or 8000 mg anti-IL-36R antibody administered as one or more intravenous or subcutaneous doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg every week (qw), every two weeks (q2w), or every four weeks (q4w), from day 0 through 4 weeks. In one exemplary embodiment, after the loading dose, maintenance or subsequent doses of 1200 mg, 1800 mg, 2400 mg, 3600 mg, 4800 mg, or 6000 mg are administered as at least one subcutaneous dose of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 2400 mg, or 3000 mg every week (qw), every two weeks (q2w), or every four weeks (q4w) from week 4 through week 8. In another embodiment, the subcutaneous dose or maintenance or subsequent dose is administered at least one week after the last loading or induction dose.

[0137] As used herein, the term "treatment phase" or "maintenance phase" refers to a treatment period that involves administering an anti-IL-36R antibody or antigen-binding portion thereof to a subject to maintain a desired therapeutic effect, e.g., improvement in symptoms associated with hidradenitis suppurativa, and will generally begin 4 weeks after an initial loading dose (administered 0-4 weeks).

[0138] The term "maintenance dose" or "treatment dose" refers to the amount of an anti-IL-36R antibody or antigen-binding portion thereof administered to a subject to maintain or continue a desired therapeutic effect. A maintenance dose may be a single dose or, alternatively, a set of doses. A maintenance dose is administered during the treatment or maintenance phase of treatment. In one embodiment, the total maintenance dose is less than the induction dose, wherein, when administered sequentially, the doses may be equal to each other. In one embodiment, the present invention provides a total maintenance dose of at least 1200, 1800 mg, 2400 mg, 3600 mg, 4800 mg, or 6000 mg administered to a subject weekly (qw), every two weeks (q2w), or every four weeks (q4w) as one or more subcutaneous doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg anti-IL-36R antibody or antigen-binding portion thereof. In one embodiment, the maintenance dose begins one or two weeks after the last loading dose and is administered weekly or every two weeks. In one embodiment, the maintenance dose is administered about four weeks after the initial loading dose. The maintenance dose can be increased or decreased to achieve the desired therapeutic goal. In a preferred embodiment, the maintenance dose is smaller and / or administered less frequently than the loading dose.

[0139] The term "maintenance therapy" or "maintenance regimen" refers to a treatment schedule for a subject or patient diagnosed with a disorder / disease, such as hidradenitis suppurativa, that maintains the subject's health in a predetermined state, e.g., reduces the number of inflammatory lesions or achieves a clinical response. In one embodiment, a maintenance therapy of the present invention is used for a subject or patient diagnosed with a disorder / disease, such as hidradenitis suppurativa, to maintain the subject's health in a state where symptoms associated with the disease have completely disappeared or are reduced. In one embodiment, a maintenance therapy of the present invention is used for a subject or patient diagnosed with a disorder / disease, such as hidradenitis suppurativa, to maintain the subject's health in a state where symptoms associated with the disease are substantially absent. In one embodiment, a maintenance therapy of the present invention is used for a subject or patient diagnosed with a disorder / disease, such as hidradenitis suppurativa, to maintain the subject's health in a state where symptoms associated with the disease are significantly reduced, and will generally be for a period starting 8 weeks after an initial loading dose (administered 0-4 weeks) and a treatment dose (administered 4-8 weeks). In one embodiment, anti-IL-36R antibody maintenance therapy can be continued after 8 weeks, including at least one subcutaneous dose, where each dose is 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, administered every two weeks (q2w) or every four weeks (q4w) after the last subcutaneous maintenance dose (e.g., at weeks 4-8). In a non-limiting exemplary embodiment, a total maintenance dose of at least 1800 mg is followed by maintenance therapy including at least one subcutaneous dose of 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg administered every two weeks (q2w) from week 8 through week 52, preferably administered every two weeks (q2w).

[0140] As used herein, the terms "biweekly dosing regimen," "biweekly administration," "q2w," and "biweekly administration" refer to the time course in which an anti-IL-36R antibody or antigen-binding portion thereof is administered to a subject to achieve a therapeutic objective, e.g., over the course of treatment. A biweekly dosing regimen is not intended to include a weekly dosing regimen. Preferably, the agent is administered every 9-19 days or every 10-18 days, more preferably every 11-17 days or every 12-16 days, even more preferably every 13-15 days, and most preferably every 14 days. In one embodiment, a biweekly dosing regimen is initiated in a subject during the 8th week of treatment. In another embodiment, a maintenance dose is administered according to a biweekly dosing regimen. In one embodiment, both the loading dose and the maintenance dose are administered according to a biweekly dosing regimen. In one embodiment, administration every two weeks includes a dosing regimen in which a dose of an anti-IL-36R antibody, or antigen-binding portion thereof, is administered to a subject every two consecutive weeks for a predetermined period of time, e.g., 4 weeks, 8 weeks, 16 weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 ​​weeks, 52 weeks, 56 weeks, etc.

[0141] The terms "qwk," "qw," or "ew," as used interchangeably herein, refer to a weekly dosing regimen in which an anti-IL-36R antibody or antigen-binding portion thereof is administered to a subject once a week (or weekly) to achieve a therapeutic objective, e.g., to treat HS. As used herein, a "weekly dosing regimen" refers to the time course over which an agent (e.g., an anti-IL-36R antibody) is administered to a subject to achieve a therapeutic objective, e.g., over the course of treatment. Weekly administration is more frequent than every two weeks, e.g., every 6-8 days, every 5-8 days, or every 7 days.

[0142] The term "intravenous infusion" refers to the introduction of a drug into a vein of an animal or human patient over a period of more than about 15 minutes, generally about 30 to 90 minutes.

[0143] The term "intravenous bolus" or "intravenous push" refers to administering a drug into an animal or human vein so that the body receives the drug within about 15 minutes, typically within 5 minutes.

[0144] 12. The method of claim 11, further comprising subcutaneously administering to the subject at least one dose of 300 mg, 600 mg, 900 mg, or 1200 mg of the anti-IL-36R antibody, comprising at least one dose of at least 1200 mg maintenance.

[0145] The term "subcutaneous administration" refers to the introduction of a drug from a drug reservoir under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow, sustained delivery. The skin can be pinched and lifted from the underlying tissue to form the pocket.

[0146] The term "subcutaneous infusion" refers to the introduction of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow, sustained delivery from a drug reservoir for a period including, but not limited to, 30 minutes or less or 90 minutes or less. Optionally, the infusion can be accomplished by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient, where the pump delivers a predetermined amount of drug for a predetermined period of time, e.g., 30 minutes, 90 minutes, or the length of the treatment regimen.

[0147] The term "subcutaneous bolus" refers to administering a drug under the skin of an animal or human patient. In this case, the bolus drug delivery is less than about 15 minutes, in another embodiment, less than 5 minutes, and in yet another embodiment, less than 60 seconds. In yet another embodiment, the drug is administered into a pocket between the skin and the underlying tissue. In this case, the pocket can be formed by pinching and lifting the skin away from the underlying tissue.

[0148] The dosing regimens described herein can be adjusted (e.g., in an individual patient) to provide the optimum desired response, e.g., maintenance of hidradenitis suppurativa remission, in light of the teachings herein.

[0149] It should be noted that dosage amounts may vary depending on the type and severity of hidradenitis suppurativa. For any particular subject, specific dosage regimens can be adjusted over time according to the teachings herein and the individual needs and professional judgment of the person administering or supervising the administration of the compositions, with the further understanding that dosage amounts and ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed invention.

[0150] A "pharmaceutical formulation" or "formulation" refers to the process and product of combining an active drug or agent with chemicals to produce a final drug product or pharmaceutical product. The final formulation thus refers to a medical product, e.g., a liquid, powder, or composition. Thus, in one embodiment, the pharmaceutical formulation is a pharmaceutical composition.

[0151] "Pharmaceutical composition" in this context refers to a liquid or solid preparation in a form that clearly allows the biological activity of the active ingredient to be exerted and that does not contain additional ingredients that are significantly toxic to the subject to which the composition will be administered. Such compositions are sterile. "Powder" refers to a freeze-dried, lyophilized, or spray-dried pharmaceutical composition for parenteral use. The powder is typically reconstituted or dissolved in water. Freeze-drying is a low-temperature dehydration process that involves freezing the product, reducing the pressure, and then removing the ice by sublimation. Freeze-drying produces high-quality products due to the low temperatures used in processing. Well-developed freeze-dried formulations maintain the shape and appearance of the product over time, and the quality of the rehydrated product is excellent. Spray-drying is another method for producing dry powders from liquids or slurries by rapid drying with hot gases, with the aim of achieving a consistent particle size distribution.

[0152] As used herein, "buffer" refers to a buffered solution that resists changes in pH due to the action of acid-base conjugate components. "pH" herein refers to the acidity or alkalinity of a composition at room temperature. Standard methods for measuring the pH of a composition are known to those skilled in the art. Typically, measuring pH involves calibrating the meter, placing the electrode in a thoroughly mixed sample, and then reading the pH directly from the pH meter. Exemplary buffers of the present invention include acetate, citrate, histidine, succinate, phosphate, and Tris.

[0153] As used herein, the term "tonicifying agent" or "tonicity agent" or "tonicifer" refers to a substance that provides an osmotic pressure equal to that of serum in the body, and includes salts (e.g., sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g., sucrose, trehalose, sorbitol, magnesium sulfate (MgSO), glycerol, mannitol, or dextrose). In addition, sugars present in the solution function as cryoprotectants for proteins, allowing the drug substance to be frozen without damage. This allows the drug substance to be shipped in a frozen state and stored for long periods of time prior to filling into the pharmaceutical product. Exemplary tonicity agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and / or sucrose, trehalose, sorbitol, magnesium sulfate (MgSO), glycerol, mannitol, or dextrose (sugars).

[0154] 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.

[0155] As used herein, the term "surfactant" refers to a substance that tends to reduce the surface tension of the liquid it is dissolved in. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0156] In an embodiment of any of the above aspects, the anti-IL-36R antibody or antigen-binding fragment thereof (as disclosed herein) is present in a stable pharmaceutical formulation (as described in co-pending US Ser. No. 16 / 809,606, filed March 5, 2020), the contents of which are incorporated herein by reference in their entirety, for administration to a mammal or patient according to any one of the aspects of the invention.

[0157] In one embodiment, the method of treatment according to any of the aspects described herein comprises administering to a mammal or patient 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 isotonic agent (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizer (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 mM to about 150 mM ... an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of an anti-IL-36R antibody ( The present invention relates to a method for treating HS, comprising administering a therapeutic amount of a stable pharmaceutical formulation comprising a pharmaceutically acceptable salt (e.g., sodium chloride) and a pharmacologically acceptable surfactant (e.g., polysorbate 20) in an amount of about 0 g / L to about 1.5 g / L, wherein hidradenitis suppurativa (HS) in a patient is treated, prevented, or ameliorated, or a skin disorder associated with HS in a patient is treated, or skin inflammation associated with HS in a patient is reduced or alleviated, or neutrophil infiltration in affected skin tissue of a subject suffering from HS in a patient is prevented and / or reduced, or microbial colonization of the skin in a subject with HS is reduced, or susceptibility to skin infection in a subject suffering from HS is reduced, and complete resolution of HS symptoms in the patient is achieved. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pH of the aqueous pharmaceutical formulation is about 5 to about 7. In a related embodiment, the pharmaceutical formulation is for intravenous administration to a mammal or a patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration contains an anti-IL-36R antibody in an amount of about 60 mg / mL, where one vial contains 450 mg. In a related embodiment, the pharmaceutical formulation for subcutaneous administration contains an anti-IL-36R antibody in an amount of about 150 mg / mL, where one pre-filled syringe contains 300 mg of the antibody for subcutaneous injection.

[0158] Treatment of hidradenitis suppurativa The term "subject" for the purpose of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0159] Hidradenitis suppurativa (HS) is an inflammatory disease characterized by recurrent, painful abscesses and fistulas. More specifically, HS is a skin disorder of the apocrine glands (sweat glands found in specific areas of the body) and hair follicles. Painful, swollen, inflammatory lesions, or lupus, develop in the groin and occasionally in the armpits and under the breasts. Hidradenitis suppurativa occurs when the outlets of apocrine glands become blocked by sweat or are unable to drain normally due to underdeveloped glands. The trapped secretions within the glands push sweat and bacteria into the surrounding tissues, causing subcutaneous induration, inflammation, and infection. Hidradenitis suppurativa is limited to areas of the body containing apocrine glands. These areas include the axillae, areola or nipples, groin, perineum, perianal, and periumbilical areas.

[0160] Individuals with HS have the lowest objective quality of life among skin diseases. Lesions characteristically occur in the axilla, groin, submammary, and / or anogenital areas of the body. HS lesions may progress to form fistulas and enlarging abscesses. Sequelae include significant pain, scarring, and psychological distress. IL-36 ligand has been shown to be upregulated in the lesioned skin and circulation of individuals with HS (Di Caprio et al., 2017; Hessam et al., 2018; Thomi et al., 2017).

[0161] Although there are no animal model data for HS, the expression and function of this pathway in various disease-related cell types are associated with skin inflammation. IL36R is expressed in epithelial cells (e.g., keratinocytes, intestinal epithelial cells), dermal fibroblasts, and immune cells (myeloid cells, B cells, and T cells). IL36R receptor-deficient mice showed significantly reduced skin inflammation and keratinocyte proliferation compared with wild-type controls.

[0162] IL36R is a novel member of the IL1R family that forms heterodimeric complexes with the IL1R accessory protein (IL1RAcp) and IL1Rrp2, which are associated with epithelial-mediated inflammation and barrier dysfunction. The heterodimeric IL36R system, with stimulatory ligands (IL36α, IL36β, IL36γ) and inhibitory ligands (IL36Ra and IL38), shares many structural and functional similarities with other members of the IL1 / IL1R family, such as IL1, IL18, and IL33. All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through unique cognate receptor proteins that, upon ligand binding, recruit the common IL1RacP subunit and activate the NFkB and MAP kinase pathways in receptor-positive cell types ( Dinarello, 2011 ; Towne et al., 2004 ; Towne et al., 2011 ).

[0163] Thus, the present invention includes a method for treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or an antigen-binding fragment thereof. As used herein, the phrase "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms of hidradenitis suppurativa (HS), such as neutrophil infiltration, pustules, etc. in affected skin tissue and / or has been diagnosed with an HS condition.

[0164] In embodiments, a subject suffering from hidradenitis suppurativa may also have a skin infection selected from the group consisting of impetigo, cellulitis, infectious dermatitis, eczema, herpes, folliculitis, infectious blisters, mycosis, tinea versicolor, Staphylococcus aureus infection, and Streptococcus infection. Microorganisms causing the infection include, but are not limited to, Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, herpes simplex virus, coxsackievirus, molluscum contagiosum virus, vaccinia virus, Candida albicans, Microsporum species, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species.

[0165] The present invention provides methods for reducing microbial colonization on the skin of a subject with hidradenitis suppurativa, comprising administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof. In certain embodiments, the present invention provides methods for reducing S. aureus colonization on the skin of an individual with neutrophilic dermatitis. In some embodiments, microbial colonization is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% compared to baseline by administering an anti-IL-36R antibody.

[0166] Microbial colonization can be measured by tests and techniques known in the art, such as PCR, microbial culture, microscopy and staining, or immunofluorescence. In certain embodiments, microbial colonization can be measured by the presence of microbial protein biomarkers known in the art, such as microbial toxins, such as staph toxic shock syndrome toxin-1. Methods for detecting and / or quantifying such biomarkers are known in the art.

[0167] As used herein, the terms "treat," "treating," and the like mean to alleviate symptoms, eliminate the cause of symptoms, either temporarily or permanently, or prevent or delay the onset of symptoms of a specified disorder or condition. These terms are meant to include therapeutic and prophylactic or suppressive measures for a disease or disorder that produce any clinically desirable or beneficial effect. The terms include, but are not limited to, alleviating or alleviating one or more symptoms of a disease or disorder, and reversing, slowing, or halting the progression of a disease or disorder. Thus, for example, the term "treatment" includes administering an agent before or after the onset of symptoms of a disease or disorder, thereby preventing or eliminating one or more signs of a disease or disorder. As another example, the term includes administering an agent after clinical symptoms of the disease have appeared to combat the symptoms of the disease. Furthermore, as used herein, "treatment" or "therapy" includes administering an agent after the onset of symptoms and clinical symptoms, where the administration affects the clinical parameters of the disease or disorder, e.g., the degree of tissue damage, regardless of whether the treatment results in improvement of the disease. Furthermore, so long as the compositions of the invention, alone or in combination with another therapeutic agent, alleviate or ameliorate at least one symptom of the disorder being treated compared to the symptom in the absence of the humanized anti-IL-36R antibody composition, the result should be considered an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated.

[0168] The term "therapeutically effective amount" is used to refer to an amount of an active agent that relieves or ameliorates one or more of the symptoms of the disorder being treated. In another embodiment, a therapeutically effective amount refers to a target serum concentration shown to be effective, for example, in slowing disease progression. Efficacy can be measured by techniques understood by those skilled in the art, for example, by the measurements and techniques described below. In this case, the proportion of individuals having a response to administration of anti-IL36R is statistically significantly higher for one or more endpoints compared to individuals to a placebo.

[0169] The term "prophylactically effective amount" refers to an amount effective, at a dosage and for a period of time necessary, to achieve a desired prophylactic result. Typically, a prophylactic dose is used in a subject before the onset of HS and / or before the onset of HS symptoms, for example, to prevent or inhibit the occurrence of HS flares. In an embodiment, the subcutaneous dose contemplated herein is a prophylactic dose used in a patient with acute HS to prevent possible recurrence of HS in the patient after an intravenous dose.

[0170] Treatment endpoints Embodiments of the present invention provide a means for treating individuals suffering from moderate to severe chronic hidradenitis suppurativa.

[0171] In other embodiments, the present invention provides improved methods of treatment, including methods of improving disease relief in individuals with hidradenitis suppurativa and methods of improving quality of life for individuals with hidradenitis suppurativa.

[0172] In other embodiments, the present invention provides methods for treating specific subpopulations of individuals, including, for example, individuals who have failed previous treatments or who have a subtherapeutic response, including subjects who have an inadequate response to, or intolerance to, oral antibiotics, or who have a contraindication to oral antibiotics. In certain embodiments, the present invention is used to treat HS in subjects who do not respond to or are intolerant of oral antibiotics for treating hidradenitis suppurativa, or in subjects who have an inadequate response to, or intolerance to, TNF-α inhibitors, or who have a contraindication to TNF-α inhibitors. In certain embodiments, the present invention is used to treat HS in subjects who have not responded to or are intolerant of TNF-α for treating hidradenitis suppurativa.

[0173] The methods and uses described herein provide a means to determine the efficacy of an anti-IL-36R antibody, or an antigen-binding portion thereof, for treating hidradenitis suppurativa, and the use of such an anti-IL-36R antibody for treating hidradenitis suppurativa. Treatment of HS can be assessed by any of the assays described herein or any assay known in the art, e.g., (a) % change from baseline in dT counts at week 12 (b) Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12 (c) Absolute change from baseline in International Hidradenitis Suppurativa Severity Scoring System (IHS4) scores at week 12 (d) Absolute change from baseline in Hidradenitis Suppurativa Area-Severity Index (HASI) score at week 12 (e) Achieving at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at Week 12. (f) Achievement of a Physician Global Assessment (PGA) score of 0 or 1 at Week 12 (g) Occurrence of complete disappearance of dT at 12 weeks (h) occurrence of at least one flare (defined as at least a 25% increase in the number of ANs with a maximum increase of two over baseline by week 12); (i) Absolute change from baseline in Dermatology Life Quality Index (DLQI) score at week 12 (j) Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at week 12 can be determined using

[0174] In another embodiment of any of the above first to seventh embodiments or aspects, the administration results in an efficacy endpoint of: (a) % change from baseline in dT counts at week 8 and / or week 16; (b) absolute change from baseline in IHS4 values ​​at week 8 and / or week 16; (c) absolute change from baseline in Hidradenitis Suppurativa Area-Severity Index (HASI) score at week 16; (d) achievement of hidradenitis suppurativa clinical response (HiSCR50) at week 16; (e) % change from baseline in abscess count at week 16; (f) achievement of at least a 50% reduction in dT counts relative to baseline at week 16; (g) achieving at least a 50% reduction in abscess counts and dT (AdT) counts compared to baseline at week 16; (h) achievement of at least a 50% reduction in ANdT counts relative to baseline at week 16; (i) achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at week 16; (j) % change from baseline in dT counts at each scheduled assessment time point; (k) achievement of at least a 50% reduction from baseline in dT counts at each scheduled assessment time point; (l) occurrence of complete disappearance of dT at each scheduled evaluation time point; (m) time to first occurrence of complete disappearance of dT during treatment; (n) % change from baseline in abscess counts at each scheduled assessment time point; (o) achievement of at least a 50% reduction from baseline in abscess counts at each scheduled evaluation time point; (p) occurrence of complete resolution of the abscess at each scheduled evaluation time point; (q) % change from baseline in total AdT counts at each scheduled assessment time point; (r) achievement of at least a 50% reduction from baseline in AdT counts at each scheduled assessment time point; (s) % change from baseline in inflammatory nodule (N) count at each scheduled assessment time point; (t) achievement of at least a 30% reduction from baseline in the patient global assessment numerical rating scale for HS pain (NRS30) at each scheduled assessment time point; (u) absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at each scheduled assessment time point; (v) absolute change from baseline in FACIT fatigue scale score at each scheduled assessment time point; (w) absolute change from baseline in Dermatology Life Quality Index (DLQI) score at each scheduled assessment time point; (x) absolute change from baseline in Patient Global Impression of Change (PGI-C) score over time; (y) absolute change from baseline in Patient Global Impression of Severity (PGI-S) score over time; (z) change from baseline in the Hidradenitis Suppurativa Odor and Drainage Scale (HODS) at each scheduled assessment time point; (aa) Change from baseline in NRS pruritus at each scheduled assessment time point; (bb) change from baseline in the Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment time point; (cc) % change from baseline in total ANdT counts at each scheduled assessment time point or (dd) Achieving at least a 50% reduction from baseline in ANdT counts at each scheduled evaluation time point One or more of the following will result:

[0175] In the above embodiment or another embodiment related to the above aspect, the proportion of individuals having a response to administration is statistically significantly higher for one or more of endpoints (a)-(j) and / or (a)-(dd) compared to individuals to a placebo.

[0176] In another embodiment related to the above embodiment, the present invention provides a method for reducing inflammatory lesion counts (AN counts) or achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) in an individual with HS, comprising systemically administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, such that AN counts are reduced. Clinical response according to the HiSCR scoring system is defined as at least a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas.

[0177] In another embodiment of the above embodiment, the subject does not experience an increase in the number of abscesses and / or an increase in the number of draining fistulas or ducts (dT) after administration of the anti-IL-36R antibody, or antigen-binding portion thereof.

[0178] In another embodiment related to the above embodiment, the present invention provides a method for reducing the severity of HS according to the International Hidradenitis Suppurativa Severity Scoring System (IHS4) score, which is the absolute change from baseline according to the IHS4 score for assessing the severity of HS. Determining the IHS4 requires counting nodules, abscesses, and draining tracts / fistulas. The absolute change from baseline, or "IHS4" score, assesses the severity of HS, and the resulting IHS4 score is calculated as follows: nodules (1x) + abscesses (2x) + draining tracts (4x). A total score of 3 or less indicates mild disease, 4-10 indicates moderate disease, and 11 or greater indicates severe disease.

[0179] In another embodiment related to the above embodiment, the present invention provides a method for improving (or alleviating) HS symptoms in a subject with hidradenitis suppurativa, as measured by the severity of HS symptoms according to the Hidradenitis Suppurativa Area-Severity Index (HASI) score, from a high score (e.g., a HASI score of 3 or higher in one or more areas) to a score with no effect or a score with minimal effect (e.g., an HS-PGA score of 0-2), comprising administering to the subject an IL-36R inhibitor, e.g., a human IL-36R antibody or an antigen-binding portion thereof, such that the HASI score improves from a high score to a score with no effect or a score with minimal effect. The HASI score is modeled after the Psoriasis Activity-Severity Index (PASI). It includes the four classic signs of HS-associated inflammation: erythema, induration, open ulcers, and drainage canals. Each HASI variable is scored using a Likert score (0-3) for a given body area. For BSA assessment, the number of palms (each palm representing 1% of the patient's BSA) involved in each body region (head, right axilla, left axilla, anterior chest, back, anterior buttocks, posterior buttocks, etc.) was assessed and converted to a percentage of that region. An area score was assigned to each region using the PASI approach (0 = none, 1 = 1-9%, 2 = 10-29%, 3 = 30-49%, 4 = 50-69%, 5 = 70-89%, 6 = 90-100%). To calculate the regional HASI score, the sum of the four clinical variable scores was multiplied by the area score for each involved region. This value was then multiplied by the percentage of BSA for that region to give the regional HASI score. The regional HASI scores were added together to give a cumulative total HASI score (range 0-72). The "HASI" combines assessments of lesion severity and affected area into a single score ranging from 0 (no disease) to 72 (severe disease).

[0180] In another embodiment related to the above embodiment, the present invention provides a method for improving (i.e., lowering) the hidradenitis suppurativa Physician's Global Assessment (HS-PGA) score. The present invention also provides a method for lowering the HS PGA score of a subject with hidradenitis suppurativa by at least about two stages, comprising administering an IL-36R inhibitor, e.g., a human IL-36R antibody or an antigen-binding portion thereof. The HS-PGA document is a physician's assessment of a patient's HS at a given time point. The HS-PGA scores the severity of a patient's disease based on the presence of abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules, scoring the patient as clear, minimal, mild, moderate to severe, or very severe (Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846-855). The "HS-PGA score" ranges from 0 to 5, where 0 is clear: no abscesses, drains, inflammatory nodules, or non-inflammatory nodules; 1 is minimal: no abscesses, drains, or inflammatory nodules and some non-inflammatory nodules; 2 is mild: no abscesses or drains and 1-4 inflammatory nodules, or one abscess or drain and no inflammatory nodules; 3 is moderate: no abscesses or drains and 5 or more inflammatory nodules, or one abscess or drain and 1 or more inflammatory nodules, or two to five abscesses or drains and fewer than 10 inflammatory nodules; 4 is severe: two to five abscesses or drains and 10 or more inflammatory nodules; and 5 is very severe: six or more abscesses or drains.

[0181] In another embodiment related to the above embodiment, the present invention provides a method for reducing the HS-PGA score of a subject with hidradenitis suppurativa from a high score (e.g., a score of 3 or higher) to a score that is not affected or that is only slightly affected (e.g., a score of 0 to 2), the method comprising administering a human IL-36R antibody to the subject so that the HS-PGA score is reduced from a high score to a score that is not affected or that is only slightly affected.

[0182] In another embodiment related to the above embodiment, the invention provides a method for reducing the HS-PGA score of a subject with hidradenitis suppurativa by at least about two stages, comprising administering a human IL-36R antibody to the subject such that the HS-PGA score is reduced by at least about two stages.

[0183] In another embodiment related to the above embodiment, the patient global assessment numerical rating scale (NRS30) of hidradenitis suppurativa (HS) pain can also be used as an index to measure the efficacy of an anti-IL-36R antibody or its antigen-binding portion in a patient or patient population with hidradenitis suppurativa. In this case, a statistically significant mean improvement in NRS30 pain score (compared to placebo) of at least 30% in a population of treated individuals indicates that the IL-36R antibody is effective in treating hidradenitis suppurativa. The HS Pain NRS is an endpoint for assessing the severity of HS-related pain in clinical trials for individuals with HS. Responses were given on an 11-point scale ranging from 0 (no HS pain) to 10 (the worst HS pain imaginable). In a related embodiment, the present invention provides a method for determining whether a human IL-36R antibody is effective in treating hidradenitis suppurativa based on improvement in NRS30 pain score.

[0184] In another embodiment related to the above embodiment, the present invention provides a method for improving a Dermatology Life Quality Index (DLQI) score in a subject with hidradenitis suppurativa from a high score (i.e., impaired quality of life) to a low score (i.e., no or little impact on quality of life), comprising administering a human IL-36R antibody to the subject so as to reduce the DLQI score from a high score to a low score. The DLQI is a 10-item quality of life questionnaire self-administered by patients, covering six domains including symptoms and emotions, 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 Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6-10 Jul 1993. Clin Exp Dermatol 1994;19:210-216). The DLQI has a one-week response period. Response categories include "not applicable" (score 0), "not at all" (score 0), "a little" (score 1), "quite a bit" (score 2), and "a great deal" (score 3). Question 7 is a "yes" / "no" question, where "yes" is scored as a 3. The total DLQI score is calculated by summing the scores for each question and ranges from 0 to 30. The higher the score, the more impaired quality of life is.

[0185] In another embodiment related to the above embodiment, the present invention provides a method for improving the Hidradenitis Suppurativa Quality of Life (HiS-QoL) score in a subject with hidradenitis suppurativa from a high score (i.e., quality of life is significantly affected) to a low score (minimal impact on quality of life), comprising administering a human IL-36R antibody to the subject in a manner that reduces the HiS-QoL score from a high score to a low score. The HiS-QoL survey is a 17-item patient-administered assessment tool for measuring HS-specific quality of life in clinical trials. The 17-item HiS-QoL included four symptom items, eight activity adjustment items, and five mental health items. Item scores are summed to generate a total ranging from 0 to 68. Higher scores indicate a more severe impact on quality of life.

[0186] In another embodiment related to the above embodiment, the present invention provides a method for improving HS symptoms or reducing the severity of HS-associated itch scored according to the Numerical Rating Scale for Itch (NRS Itch), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score to a low score. The HS Itch NRS is an endpoint for assessing the severity of HS-associated itch in clinical trials of individuals with HS. The patient's global assessment of HS itch assesses the most severe HS itch. The rating ranges from 0 (no itch) to 10 (the worst imaginable itch in HS), and this rating is a unidimensional measure of itch intensity and can be performed daily with minimal burden on the study participant. The response period is 24 hours, and responses are given on an 11-point scale ranging from 0 ("no itch") to 10 ("the worst imaginable itch"). Study participants are asked to rate the intensity of their itch using this scale.

[0187] In another embodiment related to the above embodiment, the present invention provides a method for improving HS symptoms or reducing the occurrence of drainage and odor resulting from clinical symptoms of HS according to the Hidradenitis Suppurativa Odor and Drainage Scale (HODS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score to a low score. The HODS is an eight-item scale developed to assess drainage and odor associated with HS in individuals. The HODS covers two domains: drainage (five items) and odor (three items). Response options range from 1 to 5. Higher scores indicate a worse assessment of the outcome for this construct.

[0188] In another embodiment related to the above embodiment, the present invention provides a method for reducing and / or ameliorating anxiety and / or depression in an individual with HS according to the Hospital Anxiety and Depression Scale (HADS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline to a low score. The HADS is an assessment tool for screening anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 items each for anxiety symptoms and depressive symptoms, with possible scores ranging from 0 to 21 for each subscale.

[0189] In another embodiment related to the above, the invention provides a method of improving the impact of HS on a patient's work productivity and / or overall activity according to the Work Productivity and Activity Impairment Index for HS (WPAI-HS), comprising administering a human IL-36R antibody to the subject so as to reduce the score from a high baseline score (high impact) to a low score (low impact). The WPAI-HS is a six-item assessment tool for assessing the impact of hidradenitis suppurativa on the ability to work and perform normal daily activities.

[0190] In another embodiment related to the above embodiment, the present invention provides a method for reducing the impact of HS on a patient's quality of life and / or improving the patient's overall quality of life as assessed by the EuroQol 5 dimension 5-level (EQ-5D-5L), comprising administering a human IL-36R antibody to the subject, wherein the improvement is a change from a high impact score to a low impact score. The descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, severe problem, and extreme problem. The EQ VAS records a patient's self-assessed health on a vertical visual analog scale. In this case, the endpoints are labeled "best imaginable health" and "worst imaginable health."

[0191] In another embodiment of the above embodiment, the proportion of individuals having a response to administration of anti-IL-36R is statistically significantly higher for one or more endpoints compared to individuals to placebo.

[0192] In one aspect, the invention relates to a method for treating or preventing recurrence of HS symptoms in a patient who has been treated with one or more intravenous doses of an anti-IL-36R antibody according to any one of the above aspects or embodiments, the method comprising administering to the patient one or more subcutaneous doses of a therapeutically effective amount of the anti-IL-36R antibody.

[0193] In one aspect, the invention relates to a method of achieving a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas in a patient treated with one or more doses of an anti-IL-36R antibody according to any one of the aspects of the embodiments above, comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous and / or subcutaneous doses.

[0194] In one aspect, the invention relates to a method of achieving improvement in one or more HS symptoms in a patient treated with one or more intravenous doses followed by one or more subcutaneous doses of an anti-IL-36R antibody according to any one of the above aspects or embodiments, wherein the HS symptoms comprise inflammatory lesions, abscesses, draining tracts / fistulas or drainage tracts (dT), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection, and / or HS-associated pain.

[0195] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show significant clinical improvement as measured by % change from baseline in total AN counts at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0196] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show a significant clinical improvement in HS flare incidence (flare incidence defined as at least a 25% increase in AN counts, with a minimum increase of two incidences compared to total AN counts at baseline) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0197] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of individuals show significant clinical improvement as measured by change in % change from baseline in total dT counts at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

[0198] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of individuals exhibit complete clearance of dT at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

[0199] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals achieve a clinical response as measured by a Hidradenitis Suppurativa Clinical Response Score (HiSCR), defined as at least a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0200] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show significant clinical improvement as measured by absolute change from baseline in the International Hidradenitis Suppurativa Severity Scoring System (IHS4) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0201] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show significant clinical improvement as measured by absolute change from baseline in Hidradenitis Suppurativa Area and Severity Index (HASI) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0202] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals exhibit a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0203] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals exhibit a score of 0 or 1 as measured by Physician Global Assessment (PGA) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0204] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show clinical improvement as measured by absolute change from baseline in Dermatology Life Quality Index (DLQI) score at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0205] In one embodiment of any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of individuals show clinical improvement as measured by absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

[0206] In a related embodiment, the proportion of individuals having a response to administration is statistically significantly higher for any of the stated endpoints compared to individuals to placebo.

[0207] Pharmaceutical Dosage and Administration The anti-IL-36R antibodies of the present invention are typically administered to patients as pharmaceutical compositions in which the antagonist is mixed with a pharmaceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984). The pharmaceutical composition can be formulated in any manner suitable for the intended route of administration. Examples of pharmaceutical formulations include lyophilized powders, slurries, aqueous solutions, suspensions, and sustained-release formulations (see, e.g., Hardman et al. (2001), Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY.) Suitable routes of administration include intravenous injection (including intra-arterial injection) and subcutaneous injection.

[0208] In one embodiment, the present invention provides a method for treating a subject with hidradenitis suppurativa (HS), comprising administering an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, to the subject according to a multiple variable dose schedule to treat HS, wherein the multiple variable dose schedule comprises administering at least one or more intravenous doses. In a related embodiment, each of the one or more intravenous doses comprises at least 450, 600, 900, 1200, or 1800 mg of the anti-IL-36R antibody, and wherein the total loading dose of the anti-IL-36R is at least 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2400 mg, 2700 mg, 3600 mg, 4800 mg, 5400 mg, or 7200 mg.

[0209] In another embodiment, the anti-IL-36R antibody is administered in a single intravenous dose. In another embodiment of any of the above aspects, the anti-IL-36R antibody is administered in at least one intravenous dose of 450 mg. In another embodiment of any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 600 mg. In another embodiment of any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 900 mg. In another embodiment of any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 1200 mg. In another embodiment of any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 1800 mg.

[0210] In another embodiment, 1, 2, 3, or 4 intravenous doses are administered. In another embodiment of any of the above aspects, 2, 3, or 4 intravenous doses are administered, 1, 2, 4, 6, 8, 10, or 12 weeks apart.

[0211] In another embodiment, 1, 2, 3, or 4 intravenous doses are administered and at least 1, 2, 3, 4, or 5 subcutaneous doses are administered to the subject at intervals of 1, 2, 4, 6, 8, 10, 12, 16 weeks after the last intravenous dose.

[0212] In one embodiment, the invention provides a method for treating a subject with hidradenitis suppurativa (HS), comprising administering to the subject an isolated human anti-IL-36R antibody, or an antigen-binding portion thereof, according to a multiple variable dose schedule to treat HS, wherein the multiple variable dose schedule comprises administering at least one or more intravenous doses. In a related embodiment, each of the one or more intravenous doses comprises at least 450 mg, 900 mg, 1200 mg, or 1800 mg of the anti-IL-36R antibody, and wherein the total loading dose is at least 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2400 mg, 2700 mg, 3600 mg, 4800 mg, 5400 mg, or 7200 mg. In a related embodiment, the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, including one or more intravenous doses of 450 mg, 900 mg, 1200 mg, or 1800 mg of said anti-IL-36R antibody. In a related embodiment, the anti-IL-36R antibody is administered in four intravenous doses of 450 mg; two, three, or four intravenous doses of 900 mg; two, three, or four intravenous doses of 1200 mg, or two, three, or four intravenous doses of 1800 mg. In a related embodiment, the two, three, or four intravenous doses are administered 1, 2, 3, or 4 weeks apart.

[0213] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous doses, wherein the total loading dose is at least 1200 mg, 2400 mg, or 3600 mg. In a preferred embodiment, three intravenous doses of 1200 mg are delivered at weeks 0, 1, and 2 for a total loading dose of 3600 mg.

[0214] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous doses (wherein the total loading dose is 3600 mg), followed by five subcutaneous doses of 1200 mg administered every two weeks at weeks 4, 6, 8, 10, and 12.

[0215] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous doses, wherein the total loading dose is at least 1800 mg, 3600 mg, or 7200 mg. In a non-limiting exemplary embodiment, for a total loading dose of 1800 mg, four intravenous doses of 450 mg are delivered at weeks 0, 1, and 2 and 3; for a total loading dose of 3600 mg, four intravenous doses of 900 mg are delivered at weeks 0, 1, and 2 and 3; or for a total loading dose of 7200 mg, four intravenous doses of 1800 mg are delivered at weeks 0, 1, and 2 and 3.

[0216] In one embodiment of any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous doses (wherein the total loading dose is at least 1800 mg, 3600 mg, or 7200 mg), followed by at least one subcutaneous dose of 300 mg, 600 mg, or 1200 mg weekly in weeks 4, 5, 6, and 7. In a non-limiting exemplary embodiment, for a total maintenance dose of 1200 mg, four subcutaneous doses of 300 mg are delivered weekly in weeks 4, 5, 6, and 7; for a total maintenance dose of 2400 mg, four subcutaneous doses of 600 mg are delivered weekly in weeks 4, 5, 6, and 7; or for a total maintenance dose of 3600 mg, four subcutaneous doses of 1200 mg are delivered weekly in weeks 4, 5, 6, and 7. In a related embodiment, at least one subcutaneous dose is administered after the last intravenous dose.

[0217] In one embodiment regarding the above maintenance dose, in a non-limiting exemplary schedule, the anti-IL-36R antibody is administered subcutaneously every two weeks at a dose of 600 mg or 1200 mg, followed by a final subcutaneous dose comprising the maintenance dose.

[0218] Representative examples of doses and dosing schedules of the present invention are disclosed in Tables 12 and 22 and 23.

[0219] Antibodies of the Invention The anti-IL-36R antibodies of the present invention are disclosed in US Pat. No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0220] As used herein, the term "antibody" includes immunoglobulin molecules and multimers thereof (e.g., IgM) that contain four polypeptide chains (two heavy chains (H chains) and two light chains (L chains) linked by disulfide bonds). In a typical antibody, each heavy chain contains a heavy chain variable region (herein referred to as HCVR or V H It is abbreviated as ) and a heavy chain constant region. The heavy chain constant region is divided into three domains: C H 1. C H 2 and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V L It is abbreviated as ) and a light chain constant region. The light chain constant region comprises one domain (C L 1) V H Area and V L The region can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), separated by more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present invention, the FRs of an anti-IL-36R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side comparison of two or more CDRs.

[0221] As used herein, the term "antibody" also includes antigen-binding fragments of full-length antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include natural, enzymatically derived, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained from full-length antibody molecules using, for example, any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding the variable domains and, optionally, the constant domains of the antibody. Such DNA is known and / or readily available, for example, from DNA libraries from commercial sources (including, for example, phage antibody libraries), or can be synthesized. For example, the DNA can be sequenced and manipulated using chemical or molecular biological techniques to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0222] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. As used herein, the term "antigen-binding fragment" also encompasses other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains.

[0223] An antigen-binding fragment of an antibody will typically contain at least one variable domain, which can be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H Domain and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region is a dimer, V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a monomeric V H Domain or V L It may contain a domain.

[0224] The antibodies used in the methods of the invention may be human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDRs, particularly CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, e.g., a mouse, have been grafted onto human framework sequences.

[0225] The antibodies used in the methods of the invention may be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described further below), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when animals transgenic for human Ig sequences are used) to thereby improve the V H Area and V L The amino acid sequence of the region is human germline V H Sequence and VL These are sequences that are derived from and related to sequences, but that may not occur naturally in vivo in the human antibody germline repertoire.

[0226] According to certain embodiments, the antibody used in the methods of the present invention specifically binds to IL-36R. The term "specifically binds" and the like means that the antibody or antigen-binding fragment thereof forms a relatively stable complex with the antigen 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, etc. For example, as used in the context of the present invention, an antibody that "specifically binds" to IL-36R is an antibody that binds to IL-36R or a portion thereof with a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM as measured by a surface plasmon resonance assay. D However, an isolated antibody that specifically binds human IL-36R may have cross-reactivity to other antigens, such as IL-36R molecules from other (non-human) species.

[0227] In certain exemplary embodiments of any aspect of the invention, an anti-IL-36R antibody or antigen-binding fragment thereof that can 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); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0228] In certain embodiments, the anti-IL-36R antibody or antigen-binding fragment thereof 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); and 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); or 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); and 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); or 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); and 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); or iv. 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: 105 (L-CDR2); and 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); or va) 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); and 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); or vi. 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: 140 (L-CDR2); and 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); or vii.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); and 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: 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). Includes:

[0229] In certain embodiments, the anti-IL-36R antibody or antigen-binding fragment thereof 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 Includes:

[0230] In certain embodiments, the anti-IL-36R antibody or antigen-binding fragment thereof comprises: i. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or iv. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125, or v. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126, or vi. a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or vii. a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or viii. A light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139, or ix. A light chain comprising the amino acid sequence of SEQ ID NO: 124 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 Includes:

[0231] In one aspect, described and disclosed herein are anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, as well as compositions and articles comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies, of the invention. Also described are binding agents comprising antigen-binding fragments of anti-IL-36 antibodies, particularly humanized anti-IL-36R antibodies.

[0232] In one aspect, the anti-IL-36R antibody described and disclosed herein is spesolimab.

[0233] Mode of action The anti-IL-36R antibodies of the present invention are humanized antagonistic monoclonal IgG1 antibodies that block human IL36R signaling. It is envisioned that binding of the anti-IL-36R antibodies of the present invention to IL36R will interfere with the subsequent activation of IL36R by its cognate ligands (IL36α, β, and γ) and the downstream activation of pro-inflammatory and pro-fibrotic pathways, with the aim of reducing epithelial cell / fibroblast / immune cell-mediated inflammation and interrupting inflammatory responses that promote pathogenic cytokine production.

[0234] IL-36R is also known as IL-1RL2 and IL-1Rrp2. Agonistic IL-36 ligands (α, β, or γ) have been reported to bind to the IL-36 receptor and subsequently initiate a signaling cascade by forming a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) inhibit the signaling cascade.

[0235] manufactured goods In another aspect, an article of manufacture containing materials useful for treating the disorders described above is included. The article of manufacture comprises a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes (e.g., for holding unit dosage forms). The container may be formed from a variety of materials, such as glass or plastic. The container holds a composition effective for treating a condition and may have a sterile access port. For example, the container may be an intravenous infusion bag or a vial with a stopper pierceable by a hypodermic injection needle. The active agent in the composition is a humanized anti-IL-36R antibody. A label attached to or associated with the container indicates that the composition is used for treating a selected condition. The article of manufacture may further comprise a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. Other materials desirable from a commercial and user standpoint may further be included, including other buffers, diluents, filters, needles, syringes, and package inserts containing instructions for use.

[0236] The term "package insert" is used to refer to instructions customarily included in commercial packaging of pharmaceutical products, which contain information about the indications, use, administration, contraindications and / or warnings regarding the use of such pharmaceutical products.

[0237] The present invention is further described in the following examples, which are not intended to limit the scope of the invention.

[0238] Example The following examples are intended to further illustrate certain preferred embodiments of the present disclosure and are not limiting in nature. Those skilled in the art will recognize or be able to identify numerous equivalents to the specific substances and procedures described herein.

[0239] Example 1: Phase IIa Clinical Trial: Treatment of Individuals with Hidradenitis Suppurativa the purpose Currently, adalimumab (TNFi) is the only approved biologic for HS, with a response rate of 42% to 59% on a weekly sc administration schedule, compared with a response rate of 26% to 28% with placebo. Currently available treatment options for suppressing HS, completely resolving symptoms, and preventing HS recurrence have limited efficacy and safety evidence. Additionally, compared with other inflammatory diseases, such as psoriasis, long-term safety concerns are significant for the treatment of HS. In this case, the dosing regimen of the biologic typically requires more focus. Given the above, there is a significant need for more effective and safer molecules with better dosing regimens in individuals with HS.

[0240] Expression of IL-36 alpha, beta, and gamma mRNA is upregulated in the lesional skin of HS individuals, while IL-36RN expression is decreased (Hessam S, Sand M, Gambichler T, et al. Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop. Br J Dermatol 2018;178:761-767). Increased expression of the ligand has also been confirmed by in situ hybridization staining within HS lesions. IL-36 is thought to be a central mediator upstream of the inflammatory loop, further activating keratinocytes, amplifying chemokine secretion, and leading to immune cell infiltration into the skin. Infiltrating dendritic cells (DCs) and monocytes are activated by IL-36 (internal and published data), which enhances DC antigen-presenting cell function and also induces the secretion of chemokines and cytokines that can recruit more immune cells, including neutrophils. IL-36 is a potent activator of neutrophil infiltration, and in the context of HS, neutrophils have been shown to undergo neutrophil nephrosis, leading to the secretion of AMP and type I interferons (Byrd AS, Carmona-Rivera C, O'Neil LJ, et al. Neutrophil extracellular traps, B cells, and type I interferons contribute to immune dysregulation in hidradenitis suppurativa. Sci Transl Med 2019;11). Based on the role of IL-36 in promoting both T17 and T1 responses, animal models of atopic dermatitis (AtD) have led to the hypothesis that IL-36 may be an important promoter of T17 responses in the skin of HS patients. With that in mind, spesolimab may be beneficial for the treatment of HS.

[0241] In this example, an anti-IL-36R antibody of the present invention is used to treat patients with hidradenitis suppurativa. The goal of this study is to find out whether a drug called spesolimab can help people with moderate to severe hidradenitis suppurativa.

[0242] The primary objective of this study was to estimate the effect of spesolimab compared with placebo on the mean percent change from baseline in total abscess and inflammatory nodule (AN) counts at week 12 in patients with moderate to severe HS. Secondary objectives were to evaluate the efficacy of spesolimab compared with placebo on secondary endpoints. The comparator for each efficacy objective was all treated individuals, excluding the effect of salvage therapy. Additional objectives of this study included evaluation of spesolimab efficacy, PK, additional measures of anti-drug antibodies (ADAs), and identification of specific biomarkers in individuals with HS.

[0243] HS is characterized by recurrent, painful abscesses and fistulas. Individuals with HS objectively have the lowest quality of life among skin diseases. Lesions typically occur in the axilla, groin, inframammary, or anogenital areas of the body. HS lesions may progress to form fistulas and enlarging abscesses. Sequelae include significant pain, scarring, and psychological distress. The average age of onset is in the early 20s (Zouboulis CC, Marmol V del, Mrowietz U, et al. Hidradenitis suppurativa / acne inversa: criteria for diagnosis, severity assessment, classification, and disease evaluation. Dermatology (Basel) 2015;231(2):184-190). The global prevalence of HS is reported to be 0.0003% to 4.1%. Underdiagnosis or inappropriate diagnosis is common. Overall, the prevalence of HS varies widely based on study methodology, but the disease is thought to be more common than previously thought (Saunte DM, Boer J, Stratigos A, et al. Diagnostic delay in hidradenitis suppurativa is a global problem. Br J Dermatol 2015;173(6):1546-1549).

[0244] Some of the most burdensome symptoms of HS from the patient's perspective are pain, pus drainage and explosive opening, itching, skin tightness (scarring), odor, fatigue, and flu-like symptoms. Individuals have been reported to be dissatisfied with the level of control provided by currently available treatment options. Unmet needs from the patient's perspective include the need for new medical treatments with good efficacy and tolerability profiles. Qualitative evidence indicated that the most important treatment goals from the patient's perspective were pain, pus drainage (including explosive opening), and fatigue.

[0245] In Phase IIa trial 1368.52, participants are divided into two groups: a placebo group or a spesolimab group. Participants receive spesolimab or a placebo as an intravenous infusion every week for the first three weeks. After that, participants receive spesolimab or a placebo as a subcutaneous injection every two weeks.

[0246] The primary objective of this Phase IIa trial was to estimate the effect of spesolimab compared with placebo on the mean percent change from baseline in total abscess and inflammatory nodule (AN) counts at week 12 in individuals with moderate to severe HS. Secondary objectives were to evaluate the efficacy of spesolimab compared with placebo on secondary endpoints. The comparator for each efficacy objective was all treated individuals, excluding the effect of salvage therapy.

[0247] Additional objectives of this trial were to evaluate spesolimab efficacy, PK, additional measures of anti-drug antibodies (ADA), and to explore specific biomarkers in individuals with HS.

[0248] Overall Design To demonstrate proof of concept, a parallel-group, randomized, double-blind, placebo-controlled trial was considered most appropriate. A placebo control group was needed to compare both the efficacy and safety of spesolimab in individuals with moderate to severe HS who were biologic-naïve or had failed prior TNFi treatment. A 2:1 randomization design may also help reduce the number of individuals assigned to the placebo group. Additionally, if individuals were eligible, they would be invited to enter the OLE trial, where they would receive the active agent.

[0249] A 12-week treatment period with spesolimab was chosen to evaluate sustained efficacy against flares in individuals with HS.

[0250] Three intravenous loading doses, followed by sc maintenance doses every 2 weeks, were chosen to optimize spesolimab exposure for evaluating its efficacy in HS. The intravenous loading dose was selected to maximize treatment response, duration of response, and achieve steady state early. The loading dose was also designed to allow for early onset of response. This was followed by subcutaneous maintenance doses to ensure sustained response.

[0251] Phase IIa Study 1368.52 was an international, multicenter, double-blind, placebo-controlled trial evaluating the efficacy and safety of spesolimab in individuals with moderate to severe HS. A total of 52 individuals were enrolled (36 individuals for spesolimab; 16 for placebo). After screening, individuals who met all eligibility criteria were randomized 2:1 to either the active or placebo group. Randomization was stratified by the TNFi-naive and TNFi-refractory populations. Approximately 33 individuals from the TNFi-naive and TNFi-refractory populations were planned for randomization. Primary failure of TNF treatment was defined as the lack of efficacy after at least 3 months of treatment with a TNF-alpha blocking agent, and secondary failure was defined as the loss of clinical efficacy in patients after an initial response to a TNF-alpha blocking agent.

[0252] After randomization, individuals began a 12-week treatment period (see Figure 3.A) with an iv loading dose of 3600 mg spesolimab (1200 mg iv q1w) or matching placebo, followed by an sc maintenance dose (q2w) of 1200 mg spesolimab or matching placebo.

[0253] For the ongoing open-label, long-term extension trial (1368.67), an interim analysis was conducted on individuals with HS who completed treatment in the 1368.52 trial. Individuals from the placebo arm of the 1368.52 trial received an initial IV loading dose of 1200 mg spesolimab plus sc placebo, followed by 600 mg spesolimab sc q2w. Individuals from the efficacy arm of the 1368.52 trial received an initial IV loading dose of placebo plus 600 mg spesolimab sc, followed by 600 mg spesolimab sc q2w.

[0254] Selection Criteria Individuals were to be enrolled in the trial (screened) at Visit 1 and treatment was to begin at Visit 2 if the individual met the following criteria:

[0255] Adult male or female individuals aged 18 or over

[0256] A written consent form has been signed and dated prior to the start of screening procedures in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and local law.

[0257] Moderate to severe hidradenitis suppurativa (HS) based on the International Hidradenitis Suppurativa Severity Rating System (IHS4) criteria for at least one year prior to the baseline visit, as determined by the investigator by interviewing the participant and / or reviewing their medical history (if the IHS4 score is unavailable, an equivalent score based on a scoring system such as HS-PGA or Hurley is acceptable based on the investigator's documented assessment).

[0258] HS lesions in at least two different anatomical regions (right / left axilla, groin, inframammary, perineum)

[0259] For HS, patients who have not been treated with biologics or who have not responded to TNF inhibitors (TNFi)

[0260] Inadequate response to an appropriate course of oral antibiotics appropriate for HS treatment within the past year (at the investigator's discretion). This does not apply to TNFi-refractory individuals.

[0261] Total abscess and inflammatory nodule (AN) count of 5 or more

[0262] Total number of draining fistulas less than 20. Further selection criteria apply.

[0263] Exclusion criteria If any of the following criteria applied, the individual should not have been screened or treated:

[0264] - The presence of active skin lesions other than HS that prevent evaluation of HS

[0265] Use of the following restricted drugs

[0266] Use of topical corticosteroids for HS lesions within 1 week prior to Visit 2

[0267] - Use of systemic antibiotics within 4 weeks prior to the visit

[0268] Use of systemic non-biologic immune modulators and / or immunosuppressants for HS within 4 weeks (or 5 half-lives, whichever is longer) prior to the 2nd visit

[0269] - Use of biologics within 12 weeks or 5 half-lives (whichever is longer) prior to the 2nd visit

[0270] - Use of opioid painkillers within the two weeks prior to the visit

[0271] - Use of live virus vaccines within 6 weeks prior to the 2nd visit

[0272] Previously received any immunosuppressive biologic agent other than a TNFi for HS

[0273] Previously received an interleukin-36 receptor (IL-36R) inhibitor, including spesolimab

[0274] -Treatment with an investigational chemical or biological device or investigational drug within a minimum of 30 days or 5 half-lives of the drug (whichever is longer) prior to Visit 2

[0275] Women who are pregnant, breastfeeding, or planning to become pregnant during the study. Women who stop breastfeeding before receiving the study drug do not need to be excluded from participation.

[0276] -A history of allergy / hypersensitivity to systemically administered investigational drugs or their excipients

[0277] Patients who have received an organ transplant (except for corneal transplants within 12 weeks prior to screening) or stem cell therapy (e.g., Remestemcel-L). Further exclusion criteria apply.

[0278] Related clinical trial activities All relevant trial activities are outlined in a flowchart (Figure 4). "Study Week" in the flowchart represents the end of each week (e.g., end of week 1 = D8, end of week 2 = D15, end of week 3 = D22, end of week 4 = D29, etc.). Relevant activities indicated as notes in the flowchart are further explained below.

[0279] Date of randomization / date of first dose of randomized medication. If necessary, in consultation with the sponsor, some of the assessments at Visit 2 could occur two days before or two days after the actual visit date (FN1). Individuals who discontinued study treatment early were required to attend an EoT visit as soon as possible. All individuals not enrolled in the OLE trial were expected to complete the EoT visit, the FUP1 visit 8 weeks after the last dose of study medication, and the final EoS visit 16 weeks after the last dose of study medication. For individuals enrolled in the OLE trial at Week 12, the EoT visit became the EoS visit in Study 1368-0052 (see also FN2 and FN8 and FN16).

[0280] X c is the time when a complete physical examination is indicated. t indicates the time point at which the target physical examination was indicated (FN3). To avoid the influence of blood sampling on vital measurements, vital signs were measured prior to blood sampling at all dosing visits. Additional vital sign assessments were to be performed 10 minutes after administration for sc doses and 5 minutes and 1 hour after administration for iv doses (FN4).

[0281] For women of childbearing potential, a serum pregnancy test was performed only at screening. A urine pregnancy test should have been performed at all other visits as indicated in the flowchart (Figure 4) (FN5).

[0282] At the study medication visit, blood samples for safety testing were to be collected prior to study medication administration. It was preferred, but not required, that individuals be in a fasting state for safety blood samples. If necessary, safety samples for Visit 2 were permitted to be collected within 48 hours prior to the actual visit (FN6).

[0283] Infection testing was performed at screening and at the EoT visit (FN7).

[0284] Subjects who discontinued study medication early were to attend the EoT visit as soon as possible. These individuals were to attend the FUP1 and EoS visits 8 and 16 weeks, respectively, after their last study medication dose (FN8).

[0285] At study visits for study drug administration, pre-dose PK / ADA / NAb samples were to be obtained approximately 1 hour before the start of the iv or sc infusion (FN9). Deoxyribonucleic acid (DNA) bank samples were optional. This sample collection was possible only if the patient consented by signing a separate consent form (FN10). In selected sites where ultrasound was available, ultrasound lesion assessment was required to guide the biopsy. In sites where ultrasound was unavailable, biopsies should have been performed without ultrasound guidance (FN11).

[0286] At screening, the C-SSRS baseline / screening scale was to be completed. At all subsequent visits, the "since last visit" scale was to be completed (FN12).

[0287] At visits 4, 5, 6, 7, and 8, individuals should have been provided with a 2-week diary, plus an additional 1-week buffer to capture the extra time slots between visits. Patient diaries should have been used to capture daily NRS scores, analgesic use, and other interventions to manage pain (FN13). Patient diaries returned by individuals should have been reviewed while the patient was in the clinic, and any information could have been clarified in an interview with the patient, if necessary (FN14).

[0288] Local tolerability at the administration site of spesolimab was assessed by the investigator during study drug administration visits and at the time of AE assessment by retrospective questioning since the last visit. Observed local tolerability reactions, e.g., "swelling," "induration," "warmth," and "redness," were to be reported as adverse events (FN15).

[0289] All individuals who completed week 12 of the study could be offered enrollment in OLE study 1368-0067. These individuals should not be required to complete the follow-up period and should complete the study visit at the EoT visit, which coincided with the first visit of 1368-0067 (FN16).

[0290] Demographics and Related Baseline Efficacy Parameters In both treatment groups, more female individuals (59.6% overall) were randomized than male individuals (40.4% overall), and the majority of individuals were Caucasian (67.3% overall), followed by Asian (11.5% overall) and unspecified (11.5% overall). The mean (SD) age was 35.2 (11.1) years and was similar in both treatment groups. The mean (SD) weight was 93.87 (23.18) kg, with a minimum of 53.5 kg and a maximum of 151.0 kg. The mean BMI (SD) was 32.28 (7.51) kg / m 2 and 30 kg / m in both treatment groups. 2 The mean age of patients with HS was greater than 18 years, which is characteristic and expected in this patient population with HS. Overall, 73.1% of individuals (n=38) were in the TNFi-naive population and 26.9% of individuals (n=14) were in the TNFi-refractory population.

[0291] All individuals met the target inclusion criterion of moderate to severe HS. Overall, 80.8% of individuals (n = 42) had severe HS and 19.2% of individuals (n = 10) had moderate HS at baseline according to IHS4. A significant imbalance in the mean (SD) number of inflammatory nodules was observed between treatment groups at baseline: spesolimab 9.5 (9.3), placebo 15.6 (12.2). Meanwhile, the mean number of abscesses and mean number of dT were similar between treatment groups. Nearly half of individuals (n = 24, 46.2%) had a total number of AN.

[0292] Table 4. Demographic data [Table 4] TIFF2026507877000005.tif175169

[0293] Primary outcome measure The primary efficacy endpoints in this trial were the percent change from baseline in total abscess and inflammatory nodule (AN) counts at 12 weeks.

[0294] Secondary outcome measures a. % change from baseline in draining fistula count at week 12 [Timeframe: Baseline, Week 12]

[0295] b. Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12 [Time Frame: Week 12]. HiSCR is one of the most well-known and widely used outcome assessments in clinical trials. HiSCR is defined as a reduction of at least 50% from baseline in total AN counts without an increase in the number of abscesses or draining fistulas (Kimball AB, Sobell JM, Zouboulis CC, et al. HiSCR (Hidradenitis Suppurativa Clinical Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with hidradenitis suppurativa from the placebo-controlled portion of a phase 2 adalimumab study. J Eur Acad Dermatol Venereol 2016;30:989-994). HiSCR was to be assessed at the time points mentioned in Table 6 (see also the clinical trial activity flowchart, Figure 4). Achieving a clinical response or "HiSCR" is defined as at least a 50% reduction in total AN counts relative to baseline, without an increase in the number of abscesses and draining fistulas.

[0296] c. Absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4) score at week 12 [time frame: baseline, week 12]. The IHS4 is a validated clinical scoring system for dynamically assessing the severity of HS. Determining the IHS4 requires counting nodules, abscesses, and draining tracts / fistulas, making it easy to apply in clinical trials (Zouboulis CC, Tzellos T, Kyrgidis A, et al, European Hidradenitis Suppurativa Foundation Investigator Group. Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br J Dermatol 2017;177:1401-1409). The IHS4 should have been assessed at the time points mentioned in Table 6 (see also the clinical trial activity flowchart, Figure 4). The severity of HS was assessed by the absolute change from baseline or "IHS4" score, which was calculated by multiplying the number of nodules (1x) + the number of abscesses (2x) + the number of drainage ducts (4x). A total score of 3 or less indicated mild disease, 4-10 indicated moderate disease, and 11 or more indicated severe disease.

[0297] d. Absolute change from baseline in Hidradenitis Suppurativa Area and Severity Index (HASI) score at week 12 [Timeframe: Baseline, Week 12]. HASI is modeled after the Psoriasis Activity and Severity Index (PASI). It includes the four classic signs of HS-related inflammation (erythema, induration, open ulcers, and drainage canals). Each HASI variable is scored on a Likert scale (0-3) for a given body region. For BSA assessment, the number of palms (one palm represents 1% of the patient's BSA) included in each body region (head, right axilla, left axilla, anterior chest, back, anterior buttock, posterior buttock, etc.) is assessed and converted to a percentage of that region. An area score was assigned to each region using the PASI approach (0 = none, 1 = 1–9%, 2 = 10–29%, 3 = 30–49%, 4 = 50–69%, 5 = 70–89%, 6 = 90–100%). To calculate the regional HASI score, the sum of the four clinical variable scores was multiplied by the area score for each involved region. This value was then multiplied by the percentage of BSA for that region to give the regional HASI score. The regional HASI scores were added together to give a cumulative total HASI score (range 0–72). HASI was to be assessed at the time points mentioned in Table 6 (see also the clinical trial activity flowchart, Figure 4). The "HASI" combines assessments of lesion severity and affected area into a single score ranging from 0 (no disease) to 72 (severe disease).

[0298] e. Achievement of a Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) score of 0 or 1 at Week 12 [Timeframe: Week 1]. The HS-PGA document is a physician assessment of a patient's HS at a given time point. The HS-PGA scores a patient's disease severity as clear, minimal, mild, moderate to severe, or very severe based on the presence of abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules (Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846-855). The HS-PGA was to be assessed at the time points noted in Table 6 (see also the clinical trial activity flowchart, Figure 4). The "HS-PGA score" ranges from 0 to 5. In this case, the scale is 0 (clear: no abscesses, drainage channels, inflammatory nodules, or non-inflammatory nodules), 1 (minimal: no abscesses, drainage channels, or inflammatory nodules and non-inflammatory nodules present), 2 (mild: no abscesses or drainage channels and 1-4 inflammatory nodules, or 1 abscess or drainage channel and no inflammatory nodules), 3 (moderate: no abscesses or drainage channels and 5 or more inflammatory nodules, or 1 abscess or drainage channel and 1 or more inflammatory nodules, or 2-5 abscesses or drainage channels and less than 10 inflammatory nodules), 4 (severe: 2-5 abscesses or drainage channels and 10 or more inflammatory nodules), and 5 (very severe: 6 or more abscesses or drainage channels present).

[0299] f. Achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of Hidradenitis Suppurativa (HS) Pain (NRS30) at Week 12 [Time Frame: Baseline, Week 12]. The HS Pain NRS is an endpoint for assessing the severity of HS-related pain in clinical trials for individuals with HS. The HS Pain NRS is a unidimensional measure of pain intensity that can be administered daily with minimal patient burden. The response period is 24 hours, and responses are given on an 11-point scale ranging from 0 (no HS pain) to 10 (the worst HS pain imaginable). The Pain NRS is completed by subjects in a daily diary from screening through Week 12.

[0300] g. Occurrence of complete disappearance of draining fistulas at week 12 [Timeframe: week 12]. Occurrence of at least one flare (defined as at least a 25% increase in the number of ANs with a maximum increase of two over baseline) by week 12 [Timeframe: week 12].

[0301] h. Absolute change from baseline in Dermatology Life Quality Index (DLQI) score at week 12 [Timeframe: Baseline, Week 12]. The DLQI is a 10-item patient-administered quality of life questionnaire covering six domains, including symptoms and emotions, daily activities, leisure, work and school, personal relationships, and treatments (Table 5). The response period for the DLQI is 1 week. Response categories include "not applicable" (score 0), "not at all" (score 0), "a little" (score 1), "quite a bit" (score 2), and "a great deal" (score 3). Question 7 is a "yes" / "no" question, where "yes" is scored as 3. The total DLQI score is calculated by summing the scores for each question and ranges from 0 to 30. In this case, 0–1 = no impact on the patient's life, 2–5 = mild impact, 6–10 = moderate impact, 11–20 = very significant impact, and 21–30 = extremely significant impact on the patient's life. The higher the score, the more impaired quality of life. If one question was left unanswered, this should have been scored as 0, and the total score should have been summed, usually expressed as a maximum of 30. For analyses based only on subscores, the corresponding subscore should have been considered missing. If two or more questions were left unanswered (missing values), the total DLQI score should have been treated as missing. A 4-point change from baseline is considered a clinically important difference.

[0302] Table 5: DLQI should have been analyzed based on the following six items: [Table 5]

[0303] Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Joint Ann Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6 - 10 Jul 1993. Clin Exp Dermatol 1994;19:210-216.

[0304] i. Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at week 12 [Time Frame: Baseline, Week 12]. The "HiS-QoL" is a 17-item patient-administered assessment tool for measuring HS-specific quality of life in clinical trials. The 17-item HiS-QoL included four symptom items, eight activity adjustment items, and five mental health items. Item scores were summed to generate a total ranging from 0 to 68. Higher scores indicate more severe impact on quality of life.

[0305] j. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue The FACIT-Fatigue is a 13-item questionnaire (Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes 2003;1:79; Yellen SB, Cella DF, Webster K, et al. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13(2):63-74; Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in individuals with rheumatoid arthritis. J Rheumatol 2005;32(5):811-819), assesses self-reported fatigue and its impact on daily activities and function. Responses are based on a 5-point Likert scale. For each question, responses of "not at all," "a little," "somewhat," "quite a bit," and "extremely" are available, corresponding to scores of 0, 1, 2, 3, and 4, respectively (total score range: 0-52). The minimal clinically meaningful difference (MCID) has been reported as a change score of 3-4 points (Cella D, et al. 2005). Item response time is 7 days.

[0306] k. Patient Global Impression of Change (PGI-C). The PGI-C is a single-item tool that assesses the change in HS from the start of study medication on a 5-point Likert-type scale. This tool was necessary for anchoring the endpoints to other assessment tools.

[0307] l. Patient Global Impression of Severity (PGI-S). The PGI-S is a single-item tool that assesses the severity of HS over the past week on a 4-point Likert-type scale. This tool was necessary for anchoring the endpoints to other assessment tools.

[0308] m. Occurrence of treatment-related adverse events (TEAEs) [Timeframe: up to Week 16]. The intensity of adverse events was to be assessed by the investigator and graded according to the RCTC version 2.0 developed by the Outcome Measures in Rheumatology (OMERACT) organization (Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common T Toxicity Criteria v.2.0. J Rheumatol 2007;34(6):1401-1414). For intensity / severity classification, see ISF. The intensity options were grade 1 (mild: asymptomatic or transient, short-lasting less than 1 week), grade 2 (moderate: symptomatic, lasting 1-2 weeks), grade 3 (severe: persistent symptoms, reversible, significant impairment), and grade 4 (life-threatening: risk of death, especially if persistent, significant impairment).

[0309] Table 6: Summary of efficacy endpoints [Table 6] TIFF2026507877000008.tif26169

[0310] Adverse events An AE was defined as any untoward medical occurrence, including a worsening of a pre-existing condition, in a patient receiving a drug in a clinical trial, which does not necessarily have a causal relationship to the treatment.

[0311] Thus, an AE can be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

[0312] The following were also to be recorded as AEs on the CRF and BI SAE form (if applicable): worsening of underlying disease or other pre-existing conditions; changes in vital signs, ECG, physical examination, or laboratory results (if deemed clinically relevant by the investigator).

[0313] If such abnormalities were already present before study inclusion, they should have been considered as baseline conditions and should have been collected only on the electronic CRF (eCRF).

[0314] Serious adverse events An SAE was defined as any adverse event that should have been considered serious because it resulted in death, was immediately life-threatening, resulted in persistent or significant disability / impairment, required or prolonged patient hospitalization, resulted in congenital anomaly / birth defect, or for any other reason.

[0315] In accordance with the EMA Initiative on Serious Medical Events, a list of additional AEs was developed by the BI that, by their nature, could always be considered "serious" even if they did not meet the criteria for an SAE as defined above. AEs considered "always serious" included new histological cancers and worsening of existing cancers. These were to be classified and reported as serious events regardless of the time elapsed since discontinuation of the drug.

[0316] Causality of adverse events Adverse events were judged based on their relationship to the investigational product. Medical judgment used to determine relationship should consider all relevant factors, including agreement with known AEs in the drug's known pharmacology or drug class, temporal relationship, discontinuation or rechallenge, confounding factors such as concomitant medications, comorbidities and relevant medical history, lack of alternative explanations, and evidence of a dose-response. Investigators were asked to record "yes" if they judged there was a reasonable causal relationship between the administered investigational drug and the adverse event, or "no" if they judged there was no reasonable causal relationship between the administered investigational product and the adverse event.

[0317] Adverse Events of Special Interest (AESI) Pre-specified AESIs in the CTP relate to any specific AEs identified at the project level as being of particular importance for future safety monitoring and evaluation in this trial, e.g., potential AEs based on knowledge from other compounds in the same class. AESIs specified in the CTP could be classified as serious or non-serious. All should have been reported promptly (within the same timeframes applicable to SAEs) to the sponsor's pharmacovigilance department on the SAE form.

[0318] The following AESIs have been designated in advance. Severe infections (according to the RCTC classification): These include Pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-transplant lymphoproliferative disorder (EBV), progressive multifocal leukoencephalopathy, bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi (mucormycosis [zygomycosis, rhizopus, mucor, lichtheimia], scedosporium / pseudallescheria boydii, fusarium), legionellosis, listeria These included monocytogenes (invasive only), tuberculosis, nocardiosis, nontuberculous mycobacteria, salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes zoster, strongyloidosis (hyperinfection syndrome and disseminated forms only), paracoccidioidomycosis, penicillium marneffei, sporothrix schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection (chaga disease) (disseminated only), campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due to Vibrio vulnificus), and HCV progression (Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory disease) diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis 2015;74:2107-2116).

[0319] Liver injury: Liver injury was defined by the following surrogate liver test parameters: Elevation of aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) ≥3 times the ULN accompanied by a ≥2-fold increase in total bilirubin measured in the same blood sample or samples collected within 30 days of each other; or Elevation of ALT and / or AST ≥10 times the ULN. These laboratory findings constituted a liver injury alert, and any patient exhibiting these laboratory abnormalities was required to be followed up according to the Drug-Induced Liver Injury (DILI) Checklist provided in the ISF. In the presence of clinical signs of liver injury (e.g., jaundice, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant pain) and laboratory results (ALT, AST, total bilirubin) were unavailable, the investigator should have ensured that these parameters were analyzed in unscheduled blood tests, if necessary. User-Defined AE Concepts (UDAEC):

[0320] Table 7. UDAEC definitions [Table 7]

[0321] Treatment administered Table 8. Test product spesolimab solution for infusion [Table 8]

[0322] Table 9. Placebo solutions corresponding to test products for infusion [Table 9]

[0323] Table 10. Test product spesolimab solution for injection [Table 10]

[0324] Table 11. Placebo solutions corresponding to the test products for injection [Table 11]

[0325] Individuals in the active group received a loading dose of 3600 mg spesolimab, administered intravenously at 1200 mg spesolimab three times each week (i.e., a total of three infusions of the loading dose were to be administered at weeks 0, 1, and 2). Individuals in the placebo group received intravenous administration of the matching placebo at the same scheduled time points. From weeks 4 through 10 (inclusive), individuals received sc injections of 1200 mg spesolimab or matching placebo every two weeks (i.e., a total of four injections [one injection per visit] were to be administered over a maximum of four visits).

[0326] This dose / schedule was selected to optimize spesolimab exposure for evaluating its efficacy in subjects with HS. The iv loading dose was selected to maximize treatment response, prolong response duration, and achieve steady state more quickly. The loading dose also allowed for a more rapid onset of response, possibly before 12 weeks. The iv loading dose was followed by an sc maintenance dose every 2 weeks. This dose was the maximum sc dose that could be conveniently given based on the injection volume and frequency.

[0327] Table 12: Doses and Dosage Schedules [Table 12]

[0328] result Primary endpoint analysis Key efficacy results demonstrated significant positive signals for reductions in the number of abscesses and draining fistulas at week 12, consistent with the hypothesized mechanism of action of spesolimab in HS. The observed LS mean difference (95% CI) between spesolimab and placebo for the percent change from baseline in total abscess and inflammatory nodule (AN) counts at week 12 was -4.1 (-31.7, 23.4) based on prespecified MMRM analysis. Due to the small sample size, imbalance in baseline AN counts between spesolimab and placebo, and extreme outliers in baseline AN counts, an additional MMRM analysis was performed for the categorical effect of baseline AN counts after unblinding. The corresponding LS mean (95% CI) between spesolimab and placebo was -15.6 (-43.8, 12.6). The LS mean difference (95% CI) in the % change from baseline in draining fistula count at week 12 was -96.6 (-154.5, -38.8). See Table 13.

[0329] Table 13: MMRM estimates of percent change from baseline in total abscess and inflammatory nodule (AN) counts at Week 12 - SAF (EC-H MMRM) [Table 13]

[0330] Due to the small sample size, imbalance in baseline AN counts between spesolimab and placebo, and extreme outliers in baseline AN counts, an additional MMRM analysis was performed on the categorical effect of baseline AN counts after unblinding. The corresponding LS mean (95% CI) between spesolimab and placebo was −15.6 (−43.8, 12.6).

[0331] Central efficacy endpoints Continuous secondary endpoints at week 12 were analyzed using a MMRM approach based on the estimator concepts and model specifications described for the primary endpoint. Binary secondary endpoints were assessed descriptively by treatment group using frequency tables (with 95% confidence intervals) based on the Safety Analysis Set (SAF). Where appropriate, a logistic regression model for the dichotomous endpoint at week 12 was also applied. This model included the treatment factor and stratification factor (TNFi-naive vs. TNFi-refractory population) as two categorical variables. As with the primary estimator, any dichotomous data collected after the use of any rescue therapy were truncated and then imputed using the non-response imputation method (NRI).

[0332] Continuous additional endpoints were assessed in the same manner as described for the primary endpoint. Binary additional endpoints were assessed in the same manner as described for the secondary binary endpoints. Kaplan-Meier estimates of survival / failure probability and median time-to-event were provided for time-to-event endpoints, e.g., time to first achievement of HiSCR. 95% confidence intervals were provided. Questionnaires were summarized descriptively by visit.

[0333] Secondary endpoint: Achievement of HiSCR at 12 weeks A Hidradenitis Suppurativa Clinical Response (HiSCR) is defined as a reduction in total AN counts by at least 50% without an increase in abscess and dT counts relative to baseline.

[0334] At week 12, the proportion of individuals achieving HiSCR was numerically higher in the spesolimab group compared to the placebo group. The risk difference (95% CI) was 13.8 (-12.9, 33.9). See Table 14 below.

[0335] Table 14: Percentage of patients achieving HiSCR at Week 12 - SAF (EC-H-NRI) [Table 14]

[0336] Consistency of treatment effects was examined in the same predefined subgroups as the primary endpoint. In general, results for the secondary endpoint, the proportion of patients achieving HiSCR at week 12, were comparable across subgroups. Patients with baseline dT demonstrated a better HiSCR response in the spesolimumab group than in the placebo group. Meanwhile, treatment effect estimates were generally comparable to those in the primary analysis. Overall, given the small size of many subgroups, no evidence was found for a difference in the effect of spesolimumab compared with placebo on HS treatment across all subgroups.

[0337] Secondary endpoint: Other than HiSCR The primary analysis method for the secondary endpoint was the estimated EC-H, which would have censored any values ​​observed after rescue medication was used for worsening disease, but no patients used rescue medication.

[0338] Continuous additional endpoints were assessed in the same manner as described for the primary endpoint. Binary additional endpoints were assessed in the same manner as described for the secondary binary endpoints. Kaplan-Meier estimates of survival / failure probability and median time-to-event were provided for time-to-event endpoints, e.g., time to first achievement of HiSCR. 95% confidence intervals were provided. Questionnaires were summarized descriptively by visit.

[0339] Results of additional secondary endpoints other than HiSCR are shown in Table 15.

[0340] % change from baseline in dT counts at week 12 At week 12, the spesolimab group demonstrated better clinical improvement than the placebo group. Compared to the placebo group, the LS mean difference (95% CI) was -96.6 (-154.5, -38.8). See Table 15 below. The reduction in dT counts in the spesolimab group appeared to be near-maximal as early as weeks 2 to 4 and was sustained through week 12.

[0341] Absolute change in IHS4 score from baseline to week 12 At week 12, the spesolimab group demonstrated better clinical improvement than the placebo group. The LS mean difference (95% CI) compared with the placebo group was -13.9 (-25.6, -2.3). See Table 15 below. The mean (SD) IHS4 score at baseline was 40.0 (34.2) in the placebo group and 28.2 (22.3) in the spesolimab group.

[0342] Absolute change from baseline in HASI score at week 12 At week 12, the spesolimab group demonstrated better clinical improvement than the placebo group. The LS mean difference (95% CI) compared with the placebo group was -19.8 (-36.9, -2.7). See Table 15 below. The mean (SD) HASI score at baseline was 82.1 (79.1) in the placebo group and 59.8 (49.5) in the spesolimab group.

[0343] Achieving a PGA score of 0 or 1 at week 12 At week 12, achievement of a PGA score of 0 or 1 was observed in the spesolimab group but not in the placebo group. Compared with the placebo group, the risk difference (95% CI) was 5.7 (-13.2, 18.6). See Table 15 below.

[0344] Achievement of NRS30 in the patient global assessment of HS pain at 12 weeks At week 12, a higher proportion of individuals in the spesolimab group than in the placebo group were observed to achieve a Patient Global Assessment of HS Pain NRS30. Compared to the placebo group, the risk difference (95% CI) was 17.0 (-6.7, 33.8). See Table 15 below.

[0345] Occurrence of complete disappearance of dT at 12 weeks At week 12, a higher proportion of individuals in the spesolimab group than in the placebo group experienced complete dT clearance. Compared to the placebo group, the risk difference (95% CI) was 18.3 (-7.9, 37.5). See Table 15 below.

[0346] At least one flare occurrence by week 12 (defined as at least a 25% increase in AN count with a maximum increase of two over baseline) At week 12, the risk difference (95% CI) for the occurrence of at least one flare was -9.1 (-33.1, 8.9) comparing the spesolimab group with the placebo group. See Table 15 below.

[0347] Absolute change from baseline in DLQI score at week 12 At week 12, clinical improvement was comparable in both treatment groups. Compared to the placebo group, the LS mean difference (95% CI) was -0.1 (-4.4, 4.3). See Table 15 below.

[0348] Absolute change from baseline in HiS-QoL total score at week 12 At week 12, clinical improvement was comparable in both treatment groups. Compared to the placebo group, the LS mean difference (95% CI) was 1.5 (-6.9, 9.8). See Table 15 below.

[0349] Table 15: Additional secondary endpoints other than HiSCR [Table 15] TIFF2026507877000018.tif152169

[0350] Additional endpoints related to lesion counts, including the number of abscesses, inflammatory nodules, non-inflammatory nodules, and draining fistulas From week 2 onwards, a greater proportion of individuals in the spesolimab group than in the placebo group had at least a 50% change from baseline in AN counts. Values ​​for both treatment groups diverged from week 4 onwards. In the spesolimab group, the response rate then exceeded 50%, with a maximum response of 57.1% (20 patients) seen at week 6. This response level generally persisted through week 12. At week 12, 48.6% of patients (17 patients) in the spesolimab group and 35.3% of patients (6 patients) in the placebo group achieved at least a 50% change from baseline in AN counts.

[0351] Percentage of individuals with at least a 75% change from baseline in AN counts over time based on the EN-H-NRI approach (data not shown). The curves for the two treatment groups diverged after week 2. In the spesolimab group, the response rate then increased to 40%, with a maximum response of 40.0% (14 patients) at week 8. By week 10, the proportion of responders in the spesolimab group was consistently higher than in the placebo group. Thereafter, the response rate in the spesolimab group decreased, and at week 12, similar responses were seen in both treatment groups. At week 12, 25.7% of patients (9 patients) in the spesolimab group and 29.4% of patients (5 patients) in the placebo group achieved at least a 75% change from baseline in AN counts.

[0352] The proportion of individuals with at least a 90% change from baseline in AN counts over time based on the EN-H-NRI approach was measured. Generally, a slightly higher proportion of patients in the spesolimab group had at least a 90% change from baseline in AN counts over time compared to the placebo group.

[0353] The proportion of patients with at least a 100% change from baseline in AN counts over time was measured based on the EN-H-NRI approach. Generally, a slightly higher proportion of individuals in the spesolimab group had at least a 100% change from baseline in AN counts over time compared to the placebo group. Responses in both treatment groups were similar, with at least a 90% change from baseline in AN counts over time.

[0354] The proportion of individuals experiencing complete clearance of dTs by week 12 was measured. From week 2 onwards, a greater proportion of individuals in the spesolimab group had complete clearance of dTs than in the placebo group. The values ​​for both treatment groups diverged after week 2. In the spesolimab group, the response rate increased to a maximum of 32.1% (9 patients), as seen at weeks 4 and 6. This response level declined slightly to 25.0% (7 patients) at week 8 and was then sustained through week 12.

[0355] The percent change from baseline in ANdT counts through week 12 was measured (data not shown). The curves for the two treatment groups diverged after week 1. In the spesolimab group, the LS mean (95% CI) for the percent change from baseline in total ANdT counts reached a maximum of -44.0 (-59.5, -28.5) at week 6, with greater responses observed in the spesolimab group than in the placebo group from week 1 through week 8. Thereafter, the response in the spesolimab group decreased, with similar responses seen in both treatment groups at week 10. At week 12, the LS mean difference (95% CI) for the percent change from baseline in ANdT counts comparing the spesolimab group with the placebo group was -8.8 (-32.3, 14.7).

[0356] The estimated probability of achieving HiSCR was higher in the spesolimab group than in the placebo group, based on observed case measurements (data not shown). The estimated probabilities between spesolimab and placebo began to diverge 3 weeks after randomization and remained so throughout the trial. Individuals in the spesolimab group achieved a response starting at week 1 and gradually increasing through week 11, up to a maximum of 71.4%. In the placebo group, the probability of achieving a response at week 1 was 5.9%, and at week 12 it was 47.1%.

[0357] Absolute change from baseline in IHS4 scores through week 12 was measured. In the spesolimab group, an initial improvement in IHS4 scores was observed as early as week 1. In the spesolimab group, the LS mean (95% CI) of absolute change from baseline in IHS4 scores reached -11.1 (-17.7, -4.5) after week 6, and the benefit in IHS4 scores was sustained through week 12.

[0358] The proportion of patients in the IHS4 category over time was measured. In the OC estimate, the highest proportion of patients in the spesolimab group were those with severe disease at baseline (77.1% (27 / 35)). At week 12, the highest proportion of patients was still with severe disease (50.0% (15 / 30)), while those with moderate disease (40.0% (12 / 30)) shifted slightly toward lower scores over time. In the placebo group, the highest proportion of patients was with severe disease at baseline (88.2% (15 / 17)), and at week 12, the highest proportion was with severe disease (78.6% (11 / 14)). The patient distribution did not shift over the course of the trial. The IHS4 category in the spesolimab group showed a trend toward improvement.

[0359] The absolute change from baseline in HASI scores was measured through week 12. Compared with the placebo group, HASI scores in the spesolimab group began to improve at week 2 and reached near-maximal benefit by week 6. The benefit in HASI scores for the spesolimab group was sustained through week 12.

[0360] Based on observed cases, the estimated probability of achieving a PGA score of 0 or 1 was low and comparable in both treatment groups. The separation of estimated probabilities between spesolimab and placebo began 3 weeks after randomization; however, the difference did not widen thereafter. Individuals in the spesolimab group began to respond at week 3 and achieved a response at a 5.7% (2 patients) rate by week 8; at week 12, the rate was 8.6% (3 patients). In the placebo group, the rate of achieving a response was 5.9% (1 patient) from week 9 through week 12 after randomization.

[0361] In both treatment groups, the proportion of patients with a PGA score of 0 or 1 over time was low. The proportion of patients achieving a PGA score of 0 or 1 over time is shown in Figure 11.1.3.3:2. The curves for spesolimab and placebo did not separate for the EC-H-NRI estimator.

[0362] A slightly higher proportion of patients in the spesolimab group achieved a 2 or more point reduction in PGA score at week 12 compared with the placebo group. The proportion of patients achieving a 2 or more point reduction in PGA score over time (only for patients with a baseline PGA score of 2 or greater) is shown in Figure 11.1.3.3:3. For the EC-H-NRI estimator, the curves for spesolimab and placebo showed the greatest separation in favor of spesolimab at week 6, although this difference diminished thereafter.

[0363] No patients in either treatment group used salvage therapy.

[0364] The proportion of patients achieving an NRS30 score over time was measured (data not shown). Curve separation between spesolimab and placebo began at week 1 and persisted through week 12 in favor of spesolimab, but the difference diminished temporarily from week 2 to week 4. The risk difference between spesolimab and placebo was greatest at week 1, at 22.9%.

[0365] The absolute change from baseline in DLQI scores was measured through week 12. The mean and median DLQI scores at baseline were comparable between both treatment groups. In both treatment groups, the mean absolute change from baseline in DLQI scores decreased from week 1, reaching a maximum decrease of -2.8 at week 12.

[0366] Overall, the proportion of patients achieving a DLQI total score of 0 or 1 was low and comparable between treatment groups.

[0367] The proportion of patients achieving DLQI improvement by week 12 was measured (data not shown). Overall, the proportion of patients achieving DLQI improvement was similar throughout the trial. In both treatment groups, the proportion of patients achieving DLQI improvement increased from week 1. In the spesolimab group, the proportion of patients achieving DLQI improvement reached a maximum of 44.1% (15 patients) at week 8 and was sustained through week 12. In the placebo group, the proportion of patients achieving DLQI improvement further increased gradually from week 1 to week 12, reaching a maximum of 46.7% (7 patients) at week 12.

[0368] The absolute change from baseline in HiS-QoL total score was similar in both treatment groups through week 12. In both treatment groups, the absolute change from baseline in HiS-QoL total score increased from week 1, reaching a maximum at week 8 (spesolimab 6.8, placebo 6.1).

[0369] FACIT-Fatigue scores improved by 2.7 points in the spesolimab group and 3.7 points in the placebo group at week 12. In the spesolimab group, improvement in FACIT-Fatigue scores appeared to be near-maximal as early as week 1 and sustained through week 12. In the placebo group, FACIT-Fatigue scores worsened by 1.9 points at week 1 and then improved through week 12, with a 3.7-point improvement. Details of the adjusted mean absolute change from baseline in FACIT-Fatigue scores over time based on the EC-H-MMRM approach were used for analysis (data not shown).

[0370] The proportion of patients with PGI-C scores over time was measured. In the OC estimate, the highest proportion of patients in the spesolimab group had a PGI-C score of 3 (no change) at Week 1 (68.8% of patients, 22 / 32), and at Week 12 (50.0% of patients, 15 / 30), had a PGI-C score of 2 (slightly better). The distribution of patients shifted toward lower scores over time. In the placebo group, the highest proportion of patients had a PGI-C score of 3 (no change) at Week 1 (70.6% of patients, 12 / 17), and at Week 12 (50.0% of patients, 7 / 14), had a PGI-C score of 3 (no change). The distribution of patients did not shift over the course of the trial. PGI-C scores in the spesolimab group showed a trend toward improvement.

[0371] At baseline, the highest proportion of patients in the spesolimab group (48.6% [17 / 35]) had a PGI-S score of 3 (severe), whereas the highest proportion of patients in the placebo group (47.1% [8 / 17]) had a PGI-S score of 2 (moderate). In the OC estimates, the highest proportion of patients in the spesolimab group (46.9% [15 / 32]) had a PGI-S score of 3 (severe) at week 1 and 37.9% [11 / 29] had a PGI-S score of 1 (mild) at week 12, with the distribution of patients shifting toward lower scores over time. In the placebo group, the highest proportion of patients had a PGI-S score of 2 (moderate) at week 1 (56.3%) and 7 / 14 (50.0%) at week 12 (50.0%). The patient distribution did not shift over the course of the trial. The PGI-S scores in the spesolimab group showed a trend toward improvement.

[0372] safety The proportion and incidence of patients with any AE were similar between the placebo and spesolimab groups. Approximately 4 / 5 patients reported at least one AE (placebo: 14 patients, 87.5%; spesolimab: 28 patients, 77.8%). The incidence of drug-related AEs was higher in the spesolimab group (15 patients, 41.7%) than in the placebo group (3 patients, 18.8%), primarily due to injection site reactions. No AEs leading to treatment discontinuation, other serious AEs, or SAEs occurred in the spesolimab group. In the placebo group, one patient (6.3%) reported each of an AE leading to treatment discontinuation, other serious AEs, and SAEs. No AEs leading to death, serious AEs, or AEs of particular interest as defined by the protocol (systemic hypersensitivity including infusion and anaphylactic reactions, serious infections [according to the RCTC classification], opportunistic infections, and mycobacterium tuberculosis infections or liver injury) were reported (Table 16). The proportion and incidence of patients with any AE was 65.4% during the loading phase and 80.8% throughout the entire period.

[0373] Table 16. Overall AE Summary - Safety Analysis Set [Table 16]

[0374] The most frequently reported events at the system organ class (SOC) level throughout the entire study were infections and infestations, followed by general disorders and administration site conditions, skin and subcutaneous tissue disorders, and nervous system disorders. The proportions and incidences of patients were roughly balanced between the two treatment groups in most SOCs, except for general disorders and administration site conditions and gastrointestinal disorders. The frequency and incidence of general disorders and administration site conditions was lower in the placebo group (2 patients [12.5%]) than in the spesolimab group (12 patients [33.3%]), and gastrointestinal disorders were also lower in the placebo group (1 patient [6.3%]) than in the spesolimab group (6 patients [16.7%]). All cases were classified as mild. At the preferred term (PT) level, the most frequently reported AE overall over the entire period was headache (overall: 7 patients [13.5%]; spesolimab: 4 patients [11.1%], placebo: 3 patients [18.8%]), followed by nasopharyngitis (overall: 6 patients [11.5%]; spesolimab: 3 patients [8.3%], placebo: 3 patients [18.8%]). All other PTs were reported in a maximum of 4 patients overall. At the PT level, investigator-defined drug-related AEs reported more frequently in the spesolimab group compared with the placebo group were nausea (spesolimab: 2 patients [5.6%], placebo: 0 patients [0%]), acne (spesolimab: 2 patients [5.6%], placebo: 0 patients [0%]), injection site pain (spesolimab: 3 patients [8.3%], placebo: 1 patient [6.3%]), injection site erythema (spesolimab: 3 patients [8.3%], placebo: 0 patients [0%]), and fatigue (spesolimab: 2 patients [5.6%], placebo: 0 patients [0%]). The incidence of other individual PTs was generally similar between treatment groups. Grouping of AEs defined in the trial statistical analysis plan by medical concepts defined as user-defined AE concepts was based on standardized MedDRA queries (SMQs) or, if SMQs were unavailable, a BI-specific systematic MedDRA query (BIcMQ). Among AEs classified by SMQs, angioedema, depression (excluding suicide and self-harm), and suicide / self-harm were each reported in one patient, while hypersensitivity was reported in four patients.Given the small treatment group sizes and 2:1 randomization, no meaningful numerical differences were identified between treatment groups. Among AEs classified by SMQ, anaphylactic reaction, opportunistic infection, severe infection, serious infection, malignancy, NMSC, and among AEs classified by DRESS or BIcMQ, tuberculosis infection were not reported.

[0375] Anti-drug antibodies and neutralizing antibodies Antidrug antibody (ADA) responses were determined in all patients. The immunogenicity of spesolimab was evaluated using a multi-stage approach. Briefly, all samples were first analyzed by the ADA screening assay, and only those samples that were putatively positive by the ADA screening assay were evaluated by the ADA confirmatory assay. Subsequently, only those samples that were confirmed positive were titrated (to obtain antibody titer values). Neutralizing antibody (NAb) responses were also determined in all patients who were confirmed as ADA positive.

[0376] A total of 52 patients were randomized to receive spesolimab or placebo (2:1 ratio) in this trial. Thirty-five patients received spesolimab at week 0 and 17 patients received placebo at week 0. Three patients in the spesolimab treatment group and one patient in the placebo treatment group discontinued the study drug prematurely.

[0377] For ADA assessment, baseline was defined as the study visit date if an ADA sample was collected before the first spesolimab treatment. Overall, of the 34 patients who were evaluable for ADA and were treated with spesolimab, 6 patients (17.6%) were ADA positive after treatment, and 27 patients (79.4%) were ADA negative throughout the study. Additionally, the 6 patients who were ADA positive after treatment were also ADA positive at the time of their final sample collection.

[0378] In addition, the majority of ADA-positive patients (66.7%) were also NAb-positive. In ADA-positive HS patients, ADA was detected with a median onset time of 6.00 weeks and reached maximum antibody titers at a median time of 12.0 weeks. Maximum antibody titers occurred at the time of the last sample collection. In NAb-positive patients, NAb was detected with a median onset time of 7.90 weeks. Due to the small number of NAb-positive patients in this trial, definitive conclusions regarding immunogenicity and its impact on PK could not be determined. Due to the short duration of this trial, the incidence of ADA / NAb may have been underestimated.

[0379] In HS patients with treatment-emergent ADA positivity, ADA was detected at a median time of 6.00 weeks and reached maximum antibody titers at a median time of 12.0 weeks. Maximum antibody titers occurred at the time of the last sample collection. In NAb-positive patients, NAb was detected at a median time of 7.90 weeks.

[0380] Discussion The prespecified primary analysis of this small exploratory study revealed little difference between treatment groups in the percent change from baseline in the total number of abscesses and inflammatory nodules at week 12. However, positive signals were observed at week 12 in clinically important secondary outcomes in HS: percent change from baseline in dT counts, absolute change from baseline in IHS4 (dT counts, abscess counts, and inflammation weighted counts), and absolute change from baseline in HASI (HS severity and extent). Positive trends were also observed in patients who achieved HiSCR and in patients who achieved at least a 30% reduction from baseline in the Patient Global Assessment of HS Pain NRS.

[0381] The LS mean difference (95% CI) for the percent change from baseline in dT counts at week 12 was -96.6 (-154.5, -38.8). The LS mean difference (95% CI) for the absolute change from baseline in IHS4 scores at week 12 was -13.9 (-25.6, -2.3). The LS mean difference (95% CI) for the absolute change from baseline in HASI scores was -19.8 (-36.9, -2.7). Endpoints including inflammatory nodules showed lower efficacy, but HS-related outcomes including dT counts, IHS4 scores, and HASI scores showed improvements in favor of spesolimab.

[0382] Achievement of a Patient Global Assessment of HS Pain NRS30 was observed in a higher proportion of patients in the spesolimab group than in the placebo group. The risk difference (95% CI) was 17.0 (-6.7, 33.8). Achievement of a PGA score of 0 or 1 at week 12 was observed in the spesolimab group but not in the placebo group. Numerical changes at week 12 were comparable in both treatment groups for absolute change from baseline in DLQI score at week 12 and absolute change from baseline in HiS-QoL total score at week 12.

[0383] Treatment with spesolimab demonstrated a trend toward improvement in the percent change from baseline in both AN and ANdT counts over time by week 6, but the treatment effect was not maintained through week 12. Outcomes for HS-related endpoints, including dT count, HiSCR, IHS4, and HASI, showed improvements in favor of spesolimab, but PGA-related endpoints did not demonstrate efficacy with spesolimab over the course of the study. Subjective assessments, including DLQI, HiS-QoL, and FACIT-Fatigue, did not support efficacy of spesolimab, but outcomes related to NRS30, PGI-C, and PGI-S demonstrated a trend toward improvement in the spesolimab group compared with the placebo group.

[0384] Overall, spesolimab was well tolerated in Study 1368-0052 and was generally consistent with that seen in previous spesolimab studies in other indications. The results from this clinical proof-of-concept study, particularly the high unmet medical need consistent with spesolimab's predicted mechanism of action in HS (i.e., reduction in dT counts), support further development of spesolimab in HS.

[0385] Analysis through Week 50 of an Open-Label Study of Spesolimab Following a Randomized, Placebo-Controlled Phase IIa Trial in Patients with Moderate-to-Severe HS

[0386] Objective: To describe the 1-year preliminary safety and efficacy results of open-label spesolimab treatment.

[0387] Design: Phase IIa and open-label study design. At week 24 (week 12 of OLE), patients could increase their spesolimab dose to 1200 mg SC q2w if needed (based on responder status at OLE initiation and change in HS-PGA severity since OLE initiation). HS progression was defined as a 150% increase from baseline in the number of abscesses and inflammatory nodules. Baseline refers to the last measurement before spesolimab initiation, i.e., baseline in the previous phase IIa trial in the spesolimab group or baseline in the previous OLE trial in the placebo group (Figure 8A). Patients who met the inclusion criteria also had HS lesions in two or more different body regions, a total number of abscesses and inflammatory nodules (AN) of 5 or more, a total number of drainage tracts of 20 or less, were biologic-naïve or had failed previous TNF-α inhibitor treatment for HS, and had an inadequate response to oral antibiotics for HS within the past year (Figure 8B).

[0388] Results: Spesolimab was well tolerated through 50 weeks, and the safety profile was consistent with that of the phase IIa study and other spesolimab trials. Safety analyses included patients who received spesolimab treatment for ≥1 year (n=20) and patients who discontinued treatment prematurely (n=25). Mean (SD) exposure duration: 39.1 (24.1) weeks in the previous spesolimab group and 42.9 (28.4) weeks in the previous placebo group.

[0389] A sustained reduction in total lesion counts was observed. Sustained improvements in HS severity and patient-reported outcomes were observed. Clinical benefit with spesolimab was also observed in patients who switched from placebo to spesolimab (before OLE). Figures 9A-9D show absolute changes from baseline to week 50 for lesion type and IHS4 score. At baseline, patients were n=30 on spesolimab and n=15 on placebo. For change from baseline, only patients with one or more relevant lesion types were included. At week 50, patients were n=15 on spesolimab and n=7 on placebo. Figure 9A demonstrates the mean (95% CI) absolute change from baseline in drainage duct count. Previous spesolimab group = -1.3 (-2.9, 0.3); Previous placebo group = -3.7 (0.3, -7.8) (only patients with one or more drainage ducts at baseline were included). Figure 9B demonstrates the mean (95% CI) absolute change from baseline in inflammatory nodule counts: Previous spesolimab group = -3.7 (-7.9, 0.5); Previous placebo group = -5.7 (-8.7, -2.8) (only patients with one or more inflammatory nodules at baseline were included). Figure 9C demonstrates the mean (95% CI) absolute change from baseline in abscess counts: Previous spesolimab group = -0.9 (-2.2, 0.5); Previous placebo group = -2.4 (-7.6, 2.8) (only patients with one or more abscesses at baseline were included). Figure 9D demonstrates the mean (95% CI) absolute change from baseline in IHS4 score: previous spesolimab group = -12.8 (-20.7, -5.0); previous placebo group = -23.4 (-50.8, 4.0).

[0390] Improvements in secondary and additional efficacy endpoints were sustained through week 50 and are shown in Table 17 below.

[0391] Table 17. Absolute Changes in Secondary and Additional Endpoints from Baseline to Week 50 [Table 17]

[0392] Example 2: Phase IIb-III Clinical Trial: Treatment of Patients with Moderate to Severe Hidradenitis Suppurativa The following example is a continuation of the study described in Example 1.

[0393] Objectives: Study 1368-0098 consists of two parts: a Phase IIb dose-finding study (Part 1) designed to identify the optimal dose for Phase III development in patients with moderate to severe HS. A Phase III confirmatory study (Part 2) was designed to evaluate the efficacy and safety of spesolimab in patients with moderate to severe HS. The dose-finding phase (Part 1) will characterize the dose-response curve and exposure-response relationship and help identify the dose of spesolimab that provides the most appropriate benefit / risk profile for patients with moderate to severe HS by evaluating dosing schedules.

[0394] The primary objectives of the dose-finding phase are to:

[0395] (1) To demonstrate a non-flat dose-response curve, assess quantitative treatment effect sizes, and evaluate the dose-response relationship based on the primary endpoint of % change from baseline in dT counts at week 8.

[0396] (2) To determine the optimal dose candidate for Part 2 based on the primary endpoint of % change from baseline in dT counts at Week 8, incorporating available safety and efficacy information.

[0397] Secondary objectives of the dose-finding phase are:

[0398] (1) To demonstrate a non-flat dose-response curve based on selected secondary and additional efficacy endpoints at week 8.

[0399] (2) To assess the quantitative treatment effect sizes of the % change from baseline in dT counts at week 16 and the absolute change from baseline in International Hidradenitis Suppurativa Severity Rating System (IHS4) scores at week 16.

[0400] (3) To assess the durability of efficacy of spesolimab up to 24 and 50 weeks.

[0401] (4) To evaluate the safety of spesolimab.

[0402] The objectives of the confirmation phase are to:

[0403] The confirmatory phase is designed to provide sufficient evidence of the efficacy, safety, and tolerability of spesolimab compared with placebo in study participants with moderate to severe HS.

[0404] The primary objective of the confirmatory phase (Part 2) is to demonstrate the superiority of one dosing regimen of spesolimab (identified based on analysis of Phase IIb data) (loading and maintenance doses, respectively) over placebo in the mean % change from baseline in dT counts at Week 16.

[0405] Dosing (loading and maintenance doses) for Part 2 (Phase III) is based on the primary analysis when the last study participant completes Visit 10 (Week 8).

[0406] The secondary objectives are as follows:

[0407] (1) Demonstrate superiority of spesolimab over placebo on key secondary endpoints.

[0408] (2) To evaluate the safety of spesolimab.

[0409] Overall design This international, Phase IIb / III, multicenter, double-blind, placebo-controlled, randomized clinical trial evaluates the efficacy and safety of spesolimab compared with placebo in patients with moderate to severe HS. The primary endpoint, percent change from baseline in dT counts at week 8, and the secondary endpoint, percent change from baseline in dT counts at week 16, were selected because a positive correlation between drug exposure and response (reduction in dT counts) was observed in the dose regimens tested in Studies 1368-0052 and 1368-0067 (Example 1). The draining tract is a lesion that significantly impacts study participants, and drainage represents one of the greatest unmet needs. The pathophysiology of dT suggests a potentially important role for blockade of IL-36 receptor activation by spesolimab. Based on the efficacy results in Study 1368-0052, clinical outcomes as early as week 8 are sufficient to assess the dose-exposure-response relationship for efficacy.

[0410] Absolute changes from baseline in IHS4, HASI, and HiSCR values ​​at week 8 were selected to support dT counts at week 8 (the primary endpoint for analysis).

[0411] Previous study data for spesolimab in HS indicate the need for dose-finding work and further investigation of the efficacy profile of this molecule in HS. The primary analysis will be performed after all study participants have completed the Week 8 visit. In addition, a Week 16 interim analysis will be performed after all study participants have completed the Week 16 visit. These two prespecified analyses will determine the dosing regimen selection for Part 2 and will also inform any necessary adjustments to the primary and key secondary endpoints, sample size, and study participant population. Based on the modeling results, it is understood that the loading / maintenance dosing regimen in Part 2 may differ from the dosing regimen tested by Week 8 in Part 1 and may therefore be adjusted as necessary. For example, dosing and dosing frequency can be adjusted based on the observed response and measurements of the defined primary and secondary endpoints (e.g., the potential benefit of the highest dosing regimen will be determined by data through Week 8; if benefit is not demonstrated, unnecessary overdosing through Week 16 will be limited; and study participants in the low-dose group may be escalated to a higher dose, per protocol, based on clinical response).

[0412] Approximately 200 study participants will be randomized in Part 1 (Phase IIb) and approximately 260 study participants will be randomized in Part 2 (Phase III). An overview of the study design is shown in Figures 9A and 9B.

[0413] After signing informed consent, participants will be screened for up to 28 days. If they meet all eligibility criteria, they will be randomized to one of the active groups, including high-dose, medium-dose, and low-dose groups, or placebo in a 1:1:1:1 ratio (50 participants per group). Randomization will be stratified by TNFi status (TNFi-naive vs. TNFi-exposed) and baseline dT levels (dT count ≤ 3; 4-10; > 10).

[0414] At least approximately 60 study participants from the TNFi-exposed cohort (meaning a corresponding 140 participants who are TNFi-naive) and up to approximately 100 study participants from the TNFi-exposed cohort (meaning a corresponding 100 participants who are TNFi-naive) will be randomized, respectively. These participants who have been previously exposed to TNFis may have had primary or secondary failure of TNFi treatment. Primary failure of TNF treatment is defined as the absence of benefit after at least 3 months of treatment with a TNF-α blocking agent (non-responders), and secondary failure is defined as the loss of clinical benefit in study participants after an initial response to a TNF-α blocking agent (initially responders who subsequently relapse). In addition, the TNFi-exposed cohort may have discontinued TNFis due to AEs or other reasons.

[0415] Approximately 100 study participants with a baseline dT number of 3 or less and approximately 100 study participants with a baseline dT number of 4 or more will be randomized.

[0416] Treatment Phase After randomization, study participants will begin a 50-week treatment period. Treatment administration will continue through week 48. Final assessment of treatment efficacy will occur at week 50 (EoT visit).

[0417] For the first 4 weeks, depending on the assigned dose group, study participants will receive a loading iv dose of spesolimab (either 1800 mg [high dose group], 900 mg [mid dose group], or 450 mg [low dose group]) or matching placebo weekly at Visit 2 [Week 0], Visit 3 [Week 1], Visit 4 [Week 2], and Visit 5 [Week 3].

[0418] From Visit 6 (Week 4) to Visit 9 (Week 7) (inclusive), study participants will receive a weekly maintenance sc dose of spesolimab (either 1200 mg [high-dose group], 600 mg [intermediate-dose group], or 300 mg [low-dose group], depending on the dose group assigned) or matching placebo. For study participants initially randomized to the spesolimab group, from Visit 10 (Week 8) to Visit 31 (Week 48) (inclusive), participants will receive a weekly maintenance sc dose of spesolimab (either 1200 mg (high-dose and intermediate-dose groups) or 600 mg (low-dose group) sc, depending on the dose group assigned).

[0419] From Visit 14 (Week 16), if a participant has an inadequate clinical response, defined as a 25% increase in ANdT counts compared to baseline, and the investigator agrees to a dose escalation, there is an option to increase the dose to a maximum subcutaneous dose of 1200 mg every 2 weeks (applied in an IRT-blinded manner only for participants in the low-dose treatment group).

[0420] For study participants initially randomized to the placebo group, from Visit 10 (Week 8) to Visit 13 (Week 14), inclusive, participants will receive the matching placebo every 2 weeks. From Visit 14 (Week 16) to Visit 31 (Week 48), inclusive, participants will be switched to a sc dose of spesolimab (initial 3 loading sc doses of 1200 mg spesolimab every 1 week, followed by a maintenance sc dose of 1200 mg spesolimab every 2 weeks).

[0421] From Visit 23 (Week 32) onwards, study participants will continue to receive their assigned dosing regimen or their dosing regimen will be adjusted according to the results of the primary analysis at Week 8. On this basis, the dosing regimen may be adapted from Visit 23 (Week 32) onwards.

[0422] Participants who complete the study's EoT visit (week 50) may transition into the OLE trial if they consent and meet the eligibility criteria for the OLE trial. These participants will not be required to complete the safety follow-up period, and the EoT visit will also be considered the End of Study (EoS) visit. This visit will be the first visit in the OLE trial.

[0423] Participants who permanently discontinue study medication earlier than Visit 31 (Week 48) or who are ineligible for enrollment in the OLE study for any other reason will be invited to attend an EoT visit in lieu of their next scheduled visit and will then enter the safety follow-up period (16 weeks after last medication administration).

[0424] Selection Criteria Part 1 (Phase IIb) Be of age of consent (at least 18 years of age, subject to local law) at the time of screening.

[0425] Prior to study participation, participants must sign and date a written consent form in accordance with ICH-GCP and local legislation.

[0426] Moderate to severe HS based on IHS4 criteria for at least 6 months prior to and including the baseline visit, as determined by the investigator by interviewing the participant and / or reviewing their medical history (if IHS4 scoring is not available in the pre-screening period, an equivalent scoring system such as HS-PGA or Hurley is acceptable based on the investigator's documented assessment).

[0427] HS lesions in at least two different anatomical regions (right / left axilla, right / left inguino-femoral crease, right / left inframammary crease, intermammary zone, right / left buttock, perineum, other).

[0428] For HS, biologic-naive or prior exposure to TNFi.

[0429] For biologic-naive patients, an inadequate response to an adequate course of oral antibiotics appropriate for HS treatment occurred within the past year prior to the baseline visit (at the investigator's discretion).

[0430] Total number of ANs ≥ 5 at the baseline visit.

[0431] At least one total dT count at the baseline visit.

[0432] Women of childbearing potential (WOCBP) must be able to use a highly effective method of contraception that, when used consistently and correctly, results in an annualized failure rate of less than 1% for the duration of the study and for 16 weeks after the last dose, per ICH M3(R2).

[0433] Part 2 (Phase III) Patients will need to meet the same inclusion criteria as in Part 1 (Phase IIb), except for potential criteria that will be confirmed after the primary analysis of the Phase IIb results.

[0434] Exclusion criteria Part 1 (Phase IIb) a. Participants who need or wish to continue taking restricted medications or any medications that are believed to have the potential to interfere with the safe conduct of the clinical trial.

[0435] b. History of exposure to any immunosuppressive biologic agent other than TNFi for HS.

[0436] c. History of exposure to IL-36R inhibitors, including spesolimab.

[0437] d. Has been treated with any investigational device or investigational drug of chemical or biological nature within a minimum of 30 days or 5 half-lives of the drug prior to Visit 2 (Baseline Visit), whichever is longer.

[0438] e. Women who are pregnant, breastfeeding, or planning to become pregnant during the study. Women who cease breastfeeding before receiving the study drug do not need to be excluded from participation.

[0439] f. Participants with a history of allergy / hypersensitivity to any systemically administered investigational drug or its excipients.

[0440] g. Participants who have received an organ transplant (except for corneal transplants, if done within 12 weeks prior to screening) or stem cell therapy (e.g., Remestemcel-L).

[0441] h. Participants with any documented active or suspected active malignancy or a history of malignancy within 5 years prior to the screening visit, except for adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ carcinoma of the cervix.

[0442] i. Subjects with active or latent tuberculosis (TB) should be excluded.

[0443] j. Participants with an active systemic infection within 2 weeks of Visit 2 (Baseline Visit). These participants may be re-screened at the investigator's discretion after completing treatment for the acute infection.

[0444] k. Participants with relevant chronic infections (including human immunodeficiency virus (HIV) or viral hepatitis) as determined by the investigator. Corresponding tests will be performed at screening. If the hepatitis C antibody test is positive, a positive result for the hepatitis C RNA PCR test will be considered positive. If the patient has been treated and cured of the acute infection, the patient may be re-screened.

[0445] l. Major surgery (assessed as major by the investigator) performed within 12 weeks prior to first study medication administration (Visit 2 - Baseline Visit) or planned during the study (e.g., hip replacement, aneurysmectomy, gastric ligation).

[0446] m. Participants with severe, progressive, or uncontrolled liver disease (defined as an elevation of AST, ALT, or alkaline phosphatase greater than 3 times the upper limit of normal (ULN) or an elevation of total bilirubin greater than 2 times the ULN at the Screening Visit and / or Visit 2 (Baseline Visit)). Study participants with Gilbert's Syndrome may be included unless they have an elevation of total bilirubin greater than 5 times the ULN at the Screening Visit and bilirubin fraction percentages inconsistent with a diagnosis of Gilbert's Syndrome.

[0447] n. Participant who, at the time of screening, has a severe, progressive, or uncontrolled condition, such as a renal, liver, blood, endocrine, pulmonary, cardiac, neurological, brain, or psychiatric disease (including a history or suspected history of chronic alcoholism or drug abuse) or a disease other than HS, or signs and symptoms thereof, that, in the opinion of the investigator, would compromise the participant's safety or the quality of the data and would make it difficult for the study participant to comply with the protocol, cooperate with all study visits / procedures, or complete the trial.

[0448] o. Plan to use laser or other hair removal treatments in HS affected areas during the study.

[0449] p. Participants who had either type 4 or 5 suicidal ideation on the C-SSRS in the past 12 months prior to the screening visit (i.e., active suicidal ideation with a method and intent but no specific plan or active suicidal ideation with a method, intent, and plan).

[0450] q. Participants who have engaged in any suicidal behavior (i.e., actual attempt, aborted attempt, aborted attempt, or preparatory act or behavior) in the past 2 years prior to the screening visit.

[0451] r. Have previously been enrolled in this study (Exception: Rescreened Study Participants).

[0452] s. Acute demyelinating polyneuropathy.

[0453] t. Confirmed or suspected acute SARS-CoV-2 infection. Participants who have recovered from SARS-CoV-2 infection may be eligible. The period from first symptoms or first PCR test confirmation to randomization, whichever is shorter, is 14 days or more and they have been free of SARS-CoV-2 symptoms for at least 14 days. If local criteria are more stringent, those criteria will apply.

[0454] Part 2 (Phase III) The same criteria as in Part 1 (Phase IIb) would need to be met, except for potential criteria that will be confirmed after analysis of the Phase IIb results.

[0455] Related Study Activities: See Flowchart: Part 1 (Phase IIb) (Figures 11A and 11B).

[0456] As shown in Figures 11A and 11B, visits are labeled with corresponding weeks and the ideal timeframe for the visit is indicated. Related activities indicated in the footnotes of the flowcharts (Figures 11A and 11B) are further explained below.

[0457] For Visits 7, 9, 15, 20, 22, 24, 26, 28, and 30, study participants will be offered the possibility of receiving home nursing visits, if permitted locally. In special circumstances (i.e., pandemic, conflict, etc.), visits may be conducted only by telephone to collect safety information (FN1). Study participants who discontinue study treatment early will receive an End of Treatment (EoT) visit as soon as possible. All study participants not enrolled in an open-label extension study (OLE) are expected to complete an EoT visit and an EoS visit 16 weeks after their last study medication dose or 14 weeks after EoT. For study participants enrolling in the OLE study at Week 50, the EoT visit will be the EoS visit in Study 1368-0098 (see also FN2, FN10, and FN20).

[0458] X c is the time at which a complete physical examination is provided.t indicates the time point at which the target physical exam is provided (FN3). Vital signs should be obtained prior to blood collection at all administration visits to avoid the impact of blood collection on vital measurements. Additional vital sign assessments should be performed 10 minutes after administration for sc administration and approximately 5 minutes and 1 hour after administration for iv administration (FN4).

[0459] For women of childbearing potential, a serum pregnancy test was performed at screening. A urine pregnancy test will be performed at all other visits as indicated in the flowchart (Figures 11A and 11B) (FN5).

[0460] It is preferred, but not required, that study participants be in a fasting state for blood sampling for safety testing. This should occur at the study medication visit before study medication administration (FN6).

[0461] Infection testing will be performed at screening and EoT visits (FN7).

[0462] An ECG measurement will be performed before blood sampling and drug administration. An ECG measurement will be performed at the time points indicated in the flowchart (Figures 11A and 11B). Additional ECG measurements may be performed if deemed clinically necessary by the investigator (FN8).

[0463] At study visits for study medication administration, pre-dose PK / ADA / NAb samples will be obtained approximately 2 hours before the start of the iv infusion or sc injection. At Week 0 / Day 1, post-dose PK samples will be obtained approximately 5 minutes after the end of the iv infusion (FN9). Study participants who prematurely discontinue study medication should have an EoT visit as soon as possible. These participants will then have an EoS visit 16 weeks after their last study medication dose (FN10).

[0464] Deoxyribonucleic acid (DNA) bank samples are optional. This sample collection is only possible if the trial participant consents by signing a separate consent form (FN11). Skin biopsy is mandatory at selected sites and should be sampled under ultrasound (US) guidance. At all other sites, this is optional (FN12). Lesion evaluation by US is mandatory at selected sites where US is available. At all other sites, this is optional (FN13).

[0465] The IHS4 will be used to classify the severity of the study participant's condition at baseline. The IHS4 will be obtained by lesion counting by trained medical personnel (FN14). Study participants will be provided with a study participant diary to collect daily information on NRS Pain and NRS Pruritus from baseline through Visit 19 (Week 24). After Visit 19, NRS Pain and NRS Pruritus will be collected daily for 7 days before the next scheduled visit (Visits 23, 27, 31, and EoT visits). Site staff will collect the diary from study participants at the visits indicated in the flowchart (Figures 11A and 11B) to assess pain and pruritus since the last visit (FN15).

[0466] At screening, the C-SSRS baseline / screening scale will be completed. At all subsequent visits, the "Since Last Visit" scale will be completed (FN16).

[0467] At Visit 2, participants will receive instructions for the paper version of the patient diary. Site staff should provide appropriate training. Participants will receive a 2-week diary and an additional 1-week diary to capture the extra time slots between visits. This diary will include two scales: pruritus and pain. Daily NRS pruritus and pain scores (as well as analgesic use and other interventions to manage pain) will be captured from the participant's diary until Visit 19. From Visit 23 onward, participants will record daily data on pain and pruritus for the last 7 days before their next scheduled visit (FN17a). Once electronic diaries are available, participants will receive instructions for the electronic diary. Daily NRS scores on two scales, pruritus and pain, will be captured from the participant's diary until Visit 19. From Visit 23 onwards, study participants will record data on pain and pruritus for the last 7 days before the relevant visit (once daily for the last 7 days before the next scheduled visit). Analgesic use and other interventions to manage pain will be collected at the same time points, but in paper form (FN17b). The study participant diary returned by the participant should be reviewed while the study participant is in the clinic, and any information can be clarified in an interview with the study participant, if necessary (FN18).

[0468] Local tolerability at the IMP administration site will be assessed by the investigator during study drug administration visits and at the time of AE assessment by retrospective questioning since the last visit. Observed local tolerability reactions, e.g., "swelling," "induration," "warmth," and "redness," will be assessed and reported as adverse events (FN19).

[0469] All study participants who complete Week 50 of the study may be offered enrollment in the OLE study. For these participants, the EoT visit will coincide with the EoS visit for Part 1 of Study 1368-0098 and the first visit in the OLE study (FN20).

[0470] Primary outcome measure Part 1 (Phase IIb): % change from baseline in dT counts at week 8.

[0471] Part 2 (Phase III): % change from baseline in dT counts at week 16.

[0472] Secondary outcome measures Part 1 (Phase IIb) a. % change from baseline in dT counts at week 16.

[0473] b. Absolute change from baseline in IHS4 scores at week 8.

[0474] c. Absolute change from baseline in IHS4 scores at week 16.

[0475] Part 2 (Phase III) a. Absolute change from baseline in IHS4 scores at week 16.

[0476] b. Absolute change from baseline in Hidradenitis Suppurativa Area-Severity Index (HASI) score at week 16.

[0477] c. Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR50) at week 16.

[0478] d. HiSCR50 is defined as at least a 50% reduction in the total number of abscesses and inflammatory nodules (AN) versus baseline, without an increase in abscess and dT counts.

[0479] e. % change from baseline in abscess counts at week 16.

[0480] f. Achieving at least a 50% reduction in dT counts versus baseline at Week 16.

[0481] g. Achieving at least a 50% reduction in abscess counts and dT (AdT) counts versus baseline at Week 16.

[0482] h. Achieving at least a 50% reduction in ANdT counts versus baseline at week 16.

[0483] i. Achieving at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at Week 16.

[0484] Additional Endpoints Part 1 (Phase IIb) Efficacy Lesion counts Clinical endpoints a. % change from baseline in dT counts at each scheduled assessment time point.

[0485] b. Achieving at least a 50% reduction from baseline in dT counts at each scheduled evaluation time point.

[0486] c. Occurrence of complete disappearance of dT at each scheduled evaluation time point.

[0487] d. Time to first occurrence of complete disappearance of dT during treatment.

[0488] e. % change from baseline in abscess counts at each scheduled assessment time point.

[0489] f. Achieving at least a 50% reduction from baseline in abscess counts at each scheduled evaluation time point.

[0490] g. Occurrence of complete resolution of the abscess at each scheduled evaluation time point.

[0491] h. % change from baseline in total AdT counts at each scheduled assessment time point.

[0492] i. Achieving at least a 50% reduction from baseline in AdT counts at each scheduled evaluation time point.

[0493] j. % change from baseline in inflammatory nodule (N) counts at each scheduled assessment time point.

[0494] k. % change from baseline in total ANdT counts at each scheduled assessment time point.

[0495] l. Achieving at least a 50% reduction from baseline in ANdT counts at each scheduled evaluation time point.

[0496] Response, score and flare-related clinical endpoints Achievement of HiSCR50 at each scheduled evaluation time point.

[0497] b. Absolute change from baseline in IHS4 scores at each scheduled evaluation time point.

[0498] c. Achievement of an IHS4-55 response (defined as at least a 55% reduction from baseline) at each scheduled assessment time point.

[0499] d. Absolute change from baseline in HASI score at each scheduled assessment time point.

[0500] e. Achieving a Physician Global Assessment (PGA) score of 0 or 1 at each scheduled evaluation time point.

[0501] f. Occurrence of at least one HS flare at each scheduled assessment time point: defined as an increase of at least 25% with a maximum increase of 2 over baseline in AN counts.

[0502] g. Time to first occurrence of HS redness during treatment period.

[0503] Patient-reported outcomes (PROs) Achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at each scheduled assessment time point.

[0504] b. Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at each scheduled assessment time point.

[0505] c. Absolute change from baseline in FACIT fatigue scale score at each scheduled assessment time point.

[0506] d. Absolute change from baseline in Dermatology Life Quality Index (DLQI) scores at each scheduled assessment.

[0507] e. Absolute change from baseline in Patient Global Impression of Change (PGI-C) score over time.

[0508] f. Absolute change from baseline in Patient Global Impression of Severity (PGI-S) score over time.

[0509] g. Change from baseline in Hidradenitis Suppurativa Odor and Drainage Scale (HODS) at each scheduled assessment time point.

[0510] h. Change from baseline in NRS Itch Sensation at each scheduled assessment time point.

[0511] i. Change from baseline in Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment time point.

[0512] Part 2 (Phase III): Efficacy Achievement of HiSCR50 at each scheduled evaluation time point.

[0513] b. % change from baseline in dT counts at each scheduled assessment time point.

[0514] c. Achieving at least a 50% reduction from baseline in dT counts at each scheduled evaluation time point

[0515] d. Occurrence of complete disappearance of dT at each scheduled evaluation time point.

[0516] e. Time to first occurrence of complete disappearance of dT during treatment.

[0517] f. % change from baseline in abscess counts at each scheduled assessment time point.

[0518] g. Achieving at least a 50% reduction from baseline in abscess counts at each scheduled evaluation time point.

[0519] h. Occurrence of complete resolution of the abscess at each scheduled evaluation time point.

[0520] i. % change from baseline in total AdT counts at each scheduled assessment time point.

[0521] j. Achieving at least a 50% reduction from baseline in AdT counts at each scheduled evaluation time point.

[0522] k. % change from baseline in N count at each scheduled assessment time point.

[0523] l. Absolute change from baseline in IHS4 scores at each scheduled evaluation time point.

[0524] m. Achievement of an IHS4-55 response (defined as at least a 55% reduction from baseline) at each scheduled assessment time point.

[0525] n. Absolute change from baseline in HASI score at each scheduled assessment time point.

[0526] Achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at each scheduled assessment time point.

[0527] p. % change from baseline in total ANdT counts at each scheduled assessment time point.

[0528] q. Achieving at least a 50% reduction from baseline in ANdT counts at each scheduled evaluation time point.

[0529] r. Achieving a PGA score of 0 or 1 at each scheduled evaluation time point.

[0530] s. Absolute change from baseline in HiS-QoL total score at each scheduled assessment.

[0531] t. Absolute change from baseline in FACIT fatigue scale score at each scheduled assessment time point.

[0532] u. Absolute change from baseline in DLQI score at each scheduled assessment.

[0533] v. Absolute change from baseline in PGI-C score over time.

[0534] w. Absolute change from baseline in PGI-S scores over time.

[0535] x. Change from baseline in HODS at each scheduled assessment time point.

[0536] y. Change from baseline in NRS pruritus at each scheduled assessment time point.

[0537] z. Change from baseline in HADS at each scheduled assessment time point.

[0538] aa. Occurrence of at least one HS flare at each scheduled assessment: defined as an increase of at least 25% with a maximum increase of 2 over baseline in AN counts.

[0539] bb. Time to first occurrence of HS redness during treatment period.

[0540] cc. Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS) - Change from baseline in WPAI-HS at each scheduled assessment time point.

[0541] dd.EQ-5D-5L - Change from baseline in EQ-5D at each scheduled assessment.

[0542] ee. Number of surgeries

[0543] ff. Number of days of hospitalization

[0544] gg. Number of days out of work / Number of days unemployed

[0545] hh. Number of emergency room visits

[0546] ii. Steroid-free period / remission period

[0547] jj. Period without hormone therapy (female)

[0548] kk. Antibiotic-free period / remission period

[0549] Adverse events: see discussion in Example 1 above.

[0550] Treatment administered Table 18. Test product spesolimab solution for infusion [Table 18]

[0551] Table 19. Placebo solutions corresponding to test products for infusion [Table 19]

[0552] Table 20. Test product spesolimab solution for injection [Table 20]

[0553] Table 21. Placebo solutions corresponding to test products for injection [Table 21]

[0554] Table 22: Placebo-Controlled Treatment Period Part 1 (through Visit 14 (Week 16)) [Table 22]

[0555] Part 1 (Phase IIb) Spesolimab study group up to visit 14 (week 16) a. High-dose group (1800 mg iv qw × 4, 1200 mg sc qw × 4 [including visit 9 (week 7)], then 1200 mg sc q2w until visit 14 (week 16))

[0556] b. Medium-dose group (900 mg iv qw × 4, 600 mg sc qw × 4 [including visit 9 (week 7)], then 1200 mg sc q2w until visit 14 (week 16))

[0557] c. Low-dose group (450 mg iv qw × 4, 300 mg sc qw × 4 [including visit 10 (week 8)], then 600 mg sc q2w until visit 14 (week 16))

[0558] Placebo group a. Match up to but not including Visit 14 (Week 16).

[0559] b. After Visit 14 (Week 16), participants in the placebo group will be switched to a 3600 mg sc loading dose of spesolimab (1200 mg sc qw x 3) starting with 1200 mg sc q2w by Visit 23 (Week 32).

[0560] c. After Visit 23 (Week 32), study participants will continue to receive their previously assigned dosing regimen until the primary analysis results (Week 8) are available. Once the Phase IIb primary efficacy and safety results are available, the dosing regimen may be modified and adapted after Visit 23 (Week 32).

[0561] Treatment administration will continue through week 48. A final assessment of treatment efficacy will occur at week 50 (EoT visit).

[0562] Table 23: Summary of treatment course from Visit 15 (Week 17) to Visit 31 (Week 48) [Table 23]

[0563] Spesolimab study arm from Visit 14 (Week 16) to Visit 23 (Week 32) a. From Visit 14 (Week 16) onwards, participants in the high-dose and medium-dose groups will receive 1200 mg sc q2w until Visit 23 (Week 32).

[0564] b. After Visit 14 (Week 16), participants in the low-dose group will receive 600 mg sc q2w until Visit 23 (Week 32).

[0565] c. Based on inadequate clinical response, the dose may be increased from 600 mg q2w to 1200 mg q2w, as needed (low dose group), per protocol.

[0566] From Visit 23 (Week 32) onwards, study participants will continue to receive their previously assigned dosing regimen until the primary analysis (Week 8). Based on the efficacy and safety results of the primary analysis, dosing regimens may be adapted from Visit 23 (Week 32) onwards.

[0567] placebo a. Matching until Week 16. After Week 16, participants in the placebo group will be switched to the dose schedule selected based on Phase IIb.

[0568] Treatment administration will continue through week 50. A final assessment of treatment efficacy will occur at week 52 (EoT visit).

[0569] Table 24: Dose and treatment schedule for the intravenous loading phase [Table 24]

[0570] Table 25: Subcutaneous Phase Dose and Treatment Schedule [Table 25]

[0571] result Efficacy outcomes derived from HS lesion counts include the primary endpoint proposed in Parts 1 and 2: % change from baseline in dT counts. Tracts / fistulas / sinuses should be counted as dT only if there is drainage. Other efficacy outcomes derived from lesion counts are % change from baseline for each lesion type or combination, IHS4 and HiSCR50. HASI is derived from a detailed clinical assessment of the extent and intensity of HS lesions according to specific criteria.

[0572] The HS-PGA is a brief global clinical assessment.

[0573] The study will assess efficacy according to patient-reported outcomes, including assessment of skin pain, pruritus, drainage and odor, and the Dermatology Quality of Life Index, HiS-QoL.

[0574] The descriptions of the specific scores, measures or PROs used as efficacy outcomes have been previously described in the definitions and description of the Phase IIa trial in Example 1, and specifically include the following: International Hidradenitis Suppurativa Severity Scoring System (IHS4), Hidradenitis Suppurativa Clinical Response (HiSCR50), Hidradenitis Suppurativa Area-Severity Index (HASI), Hidradenitis Suppurativa-Physician Global Assessment (HS-PGA), Numerical Rating Scale for Pain (NRS-Pain), Dermatology Quality of Life Index (DLQI), Hidradenitis Suppurativa Quality of Life (HiS-QoL), Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue), Patient Global Impression of Change (PGI-C), and Patient Global Impression of Severity (PGI-S).

[0575] Additional assessment tools include the Numerical Rating Scale for Pruritus (NRS Pruritus), Hospital Anxiety and Depression Scale (HADS) and Hidradenitis Suppurativa Odor and Drainage Scale (HODS), Hospital Anxiety and Depression Scale (HADS), described below.

[0576] Numerical Rating Scale for Pruritus (NRS Pruritus): The HS Pruritus NRS is an endpoint for assessing the severity of HS-associated pruritus in clinical trials for patients with HS. The Patient Global Assessment of HS Pruritus assesses the most severe itch. Ratings range from 0 (no itch) to 10 (the most severe itch imaginable for HS). It is a unidimensional measure of itch intensity and can be administered daily with minimal burden to study participants. The response period is 24 hours, and responses are given on an 11-point scale ranging from 0 ("no itch") to 10 (the most severe itch imaginable). Study participants are asked to rate the intensity of their itch using this scale.

[0577] Hidradenitis Suppurativa Odor and Drainage Scale (HODS): The HODS is an 8-item scale developed to assess the drainage and odor associated with HS in patients. The HODS covers two domains: drainage (5 items) and odor (3 items). Response options range from 1 to 5. Higher scores indicate a worse assessment of the outcome for this construct.

[0578] Hospital Anxiety and Depression Scale (HADS): The HADS is an assessment tool for screening anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 for anxiety symptoms and 7 for depression symptoms, with possible scores ranging from 0 to 21 for each subscale.

[0579] Additional assessment tools included only in Part 2 (Phase III) included the Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS) and the EuroQol 5 dimensions 5-level (EQ-5D-5L), described below.

[0580] Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS): The WPAI-HS is a six-item assessment tool to assess the impact of hidradenitis suppurativa on the ability to work and carry out normal daily activities.

[0581] EuroQol 5 dimensions 5-level (EQ-5D-5L): Assessment of changes in quality of life using EuroQol-5D-5L. The descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records patients' self-assessed health status on a vertical visual analog scale. In this case, the endpoints are labeled "best imaginable health" and "worst imaginable health."

[0582] statistical methods Part 1 (Phase IIb) The primary analysis of the primary endpoint consisted of an MCPMod-based test for non-flat dose-response curves combined with a quantitative treatment benefit assessment.

[0583] To account for the repeatability of the data and the covariates in the model, a MMRM analysis will be performed based on the MCPMod analysis.

[0584] The % change from baseline in dT counts will be used as the response variable in the MMRM. The MMRM will include categorical fixed effects of treatment at each visit, TNFi status at baseline, and categorical baseline dT counts at each visit. Visits will be treated as repeated measures, and an unstructured covariance structure will be used to model within-patient measurements.

[0585] Part 2 (Phase III) The primary endpoint will be the % change from baseline in dT counts at week 16. Restricted maximum likelihood estimation based on a mixed-effects model for repeated measures analysis will be used to obtain adjusted means for treatment effects. The model will include categorical fixed effects of treatment at each visit, TNFi status at baseline, and categorical baseline dT counts at each visit. The primary treatment comparison will be the contrast between treatments at week 16.

[0586] Significance tests will be based on adjusted treatment differences using a one-sided alpha of 0.025.

[0587] safety Safety will be assessed descriptively based on the following observations and tests, as previously described in Example 1: physical examination, vital signs, clinical laboratory values ​​(hematology, clinical chemistry, coagulation, infection tests, and urinalysis), 12-lead ECG, AEs, serious AEs (SAEs), AE intensity as assessed by the CTCAE classification version 5.0, and suicidal ideation. Physical examinations will be performed at the time points specified in the flowchart (Figures 11A and 11B).

[0588] Part I and Part II: Occurrence of treatment-emergent adverse events (TEAEs) Additional Purposes Additional objectives are to evaluate efficacy, including effect size through week 16, pharmacokinetics (PK), further measures of spesolimab immunogenicity (anti-drug antibodies [ADAs] and neutralizing antibodies [NAbs]), and to explore biomarkers of changes in the HS and IL-36 pathways after treatment (evaluating gene expression levels in skin biopsies and whole blood, and evaluating serum proteomic and imaging markers obtained by ultrasound [US]).

[0589] Discussion The primary objectives of the dose-finding phase were to demonstrate a non-flat dose-response curve, assess quantitative treatment effect sizes, and evaluate the dose-response relationship based on the primary endpoint of percent change from baseline in dT counts at Week 8. In addition, the dose-finding phase was used to determine the optimal dose for Part 2 by incorporating available safety and efficacy information based on the primary endpoint of percent change from baseline in dT counts at Week 8. The efficacy of spesolimab will be evaluated based on the percent change from baseline in dT counts at Weeks 8 and 16, the absolute change from baseline in IHS4 at Week 8, and the absolute change from baseline in IHS4 at Week 16.

[0590] Key secondary endpoints can be used to demonstrate efficacy, including absolute change from baseline in IHS4 scores at week 16; absolute change from baseline in Hidradenitis Suppurativa Area and Severity Index (HASI) score at week 16; achievement of Hidradenitis Suppurativa Clinical Response (HiSCR50) at week 16; % change from baseline in abscess counts at week 16; achievement of at least a 50% reduction from baseline in dT counts at week 16; achievement of at least a 50% reduction from baseline in abscess counts and dT (AdT) counts at week 16; achievement of at least a 50% reduction from baseline in ANdT counts at week 16 and achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at week 16.

[0591] Secondary objectives were to demonstrate a non-flat dose-response curve based on selected secondary and additional efficacy endpoints at a given week, evaluate the quantitative treatment effect sizes of the % change from baseline in dT counts at week 16 and the absolute change from baseline in International Hidradenitis Suppurativa Severity System (IHS4) scores at week 16, assess the durability of spesolimab efficacy through weeks 24 and 50, and evaluate the safety of spesolimab.

[0592] The primary objective of the confirmatory phase is to demonstrate that one dosing regimen of spesolimab (loading and maintenance doses) (identified based on analysis of Phase IIb data) is superior to placebo in mean % change from baseline in dT counts at Week 16.

[0593] While specific aspects and embodiments of the present invention have been described, they have been presented by way of example only and are not intended to limit the scope of the invention. Indeed, the novel methods and systems described herein may be embodied in a variety of other forms without departing from the spirit thereof. The accompanying claims and their equivalents are intended to cover such forms or modifications as would be within the scope and spirit of the invention.

[0594] All publications, including patents and / or journal articles, cited in this disclosure are expressly incorporated herein by reference.

Claims

1. 1. A method of treating, preventing, or ameliorating hidradenitis suppurativa (HS) in a patient, comprising: administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody; wherein the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, and the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of said anti-IL-36R antibody. method.

2. 1. A method of treating moderate to severe HS in a patient, comprising: administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody; wherein the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, and the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of said anti-IL-36R antibody. method.

3. 1. A method of reducing or alleviating a sign or symptom of HS in a patient, comprising: administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody; wherein the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, and the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of said anti-IL-36R antibody. method.

4. 1. A method for reducing the severity and duration of HS, comprising: administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody; wherein the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, and the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of said anti-IL-36R antibody. method.

5. 1. A method of treating a skin disorder associated with HS, comprising: administering to the patient or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody; wherein the anti-IL-36R antibody is administered at a loading dose of at least 1800 mg, and the loading dose comprises one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of said anti-IL-36R antibody. method.

6. The method of any one of claims 1 to 5, 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); and 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).

7. The anti-IL-36R antibody 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: 102 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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); b) 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); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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); c) 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); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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); d) 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); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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); e) 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); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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); f) 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); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3), and 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). The method of any one of claims 1 to 6, comprising:

8. The anti-IL-36R antibody a) 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 b) 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 c) 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 d) 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 e) 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 f) 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 g) 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 h) 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 i) 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 j) 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 The method of any one of claims 1 to 7, comprising:

9. The anti-IL-36R antibody a) a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or b) a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or c) a light chain comprising the amino acid sequence of SEQ ID NO: 115 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or d) a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or e) a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or f) a light chain comprising the amino acid sequence of SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or g) a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or h) a light chain comprising the amino acid sequence of SEQ ID NO: 123 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; or i) a light chain comprising the amino acid sequence of SEQ ID NO: 124 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 The method of any one of claims 1 to 8, comprising:

10. The method of any one of claims 1 to 9, wherein the anti-IL-36R antibody or antigen-binding portion thereof is spesolimab.

11. The method of any one of claims 1 to 10, wherein the anti-IL-36R antibody is administered in four intravenous or subcutaneous doses of 450 mg.

12. The method of any one of claims 1 to 11, wherein the anti-IL-36R antibody is administered in three or four intravenous or subcutaneous doses of 600 mg.

13. The method of any one of claims 1 to 12, wherein the anti-IL-36R antibody is administered in two, three, or four intravenous or subcutaneous doses of 900 mg.

14. The method of any one of claims 1 to 13, wherein the anti-IL-36R antibody is administered in two, three, or four intravenous or subcutaneous doses of 1200 mg.

15. The method of any one of claims 1 to 14, wherein the anti-IL-36R antibody is administered in two, three, or four intravenous or subcutaneous doses of 1800 mg.

16. The method of any one of claims 1 to 15, wherein the anti-IL-36R antibody is administered in two, three, or four intravenous or subcutaneous doses of 2000 mg.

17. The method of any one of claims 1 to 16, wherein the anti-IL-36R antibody is administered in one or two intravenous or subcutaneous doses of 2400 mg.

18. The method of any one of claims 1 to 17, wherein the anti-IL-36R antibody is administered in one or two intravenous or subcutaneous doses of 3000 mg.

19. 19. The method of any one of claims 1 to 18, wherein 2, 3 or 4 intravenous or subcutaneous loading doses are administered at intervals of qw, q2w or q4w.

20. 20. The method of any one of claims 1 to 19, further comprising subcutaneously administering to the subject a maintenance dose of at least 1200 mg after the final loading dose, wherein the maintenance dose comprises at least one dose of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg of the anti-IL-36R antibody.

21. 21. The method of claim 20, wherein the maintenance dose of anti-IL-36R antibody is administered in at least four subcutaneous doses of 300 mg; three to four subcutaneous doses of 450 mg; two to four subcutaneous doses of 600 mg; two to four subcutaneous doses of 900 mg; one to four subcutaneous doses of 1200 mg; one to four subcutaneous doses of 1800 mg; one to two subcutaneous doses of 2400 mg, or one to two subcutaneous doses of 3000 mg.

22. 21. The method of claim 20, wherein the maintenance doses of anti-IL-36R antibody are delivered subcutaneously qw, q2w, or q4w at 4, 5, 6, and / or 7 weeks after the last intravenous dose.

23. The method of claim 20, further comprising a maintenance therapy comprising subcutaneously administering 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg of the anti-IL-36R antibody to the subject every two weeks after the last dose of the maintenance dose phase and / or at the beginning after 8 weeks.

24. The administration resulted in the following efficacy endpoints: a) % change from baseline in dT counts at weeks 8 and / or 16; b) absolute change from baseline in IHS4 scores at weeks 8 and / or 16; c) Absolute change from baseline in Hidradenitis Suppurativa Area Severity Index (HASI) score at Week 16; d) Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR50) at Week 16; e) % change from baseline in abscess counts at week 16; f) Achieving at least a 50% reduction in dT counts versus baseline at week 16; g) Achieving at least a 50% reduction in abscess counts and dT counts versus baseline at week 16; h) Achieving at least a 50% reduction in ANDT counts versus baseline at Week 16; i) Achieving at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at Week 16; j) % change from baseline in dT counts at each scheduled assessment time point; k) Achieving at least a 50% reduction from baseline in dT counts at each scheduled evaluation time point; l) occurrence of complete clearance of dT at each scheduled evaluation time point; m) Time to first occurrence of complete clearance of dT during treatment; n) % change from baseline in abscess counts at each scheduled assessment time point; o) Achieving at least a 50% reduction from baseline in the number of abscesses at each scheduled evaluation time point; p) occurrence of complete resolution of the abscess at each scheduled evaluation time point; q) % change from baseline in total AdT counts at each scheduled assessment time point; r) Achieving at least a 50% reduction from baseline in AdT counts at each scheduled evaluation time point; s) % change from baseline in inflammatory nodule (N) count at each scheduled assessment time point; t) Achievement of at least a 30% reduction from baseline in the Numerical Rating Scale for Patient Global Assessment of HS Pain (NRS30) at each scheduled assessment time point; u) absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at each scheduled assessment; v) absolute change from baseline in FACIT fatigue scale score at each scheduled assessment time point; w) absolute change from baseline in Dermatology Life Quality Index (DLQI) score at each scheduled assessment; x) absolute change from baseline in Patient Global Impression of Change (PGI-C) score over time; y) absolute change from baseline in Patient Global Impression of Severity (PGI-S) score over time; z) Change from baseline in the Hidradenitis Suppurativa Odor and Drainage Scale (HODS) at each scheduled assessment time point aa) Change from baseline in NRS pruritus at each scheduled assessment time point; bb) change from baseline in Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment; cc) % change from baseline in total ANDT counts at each scheduled assessment time point or dd) Achieving at least a 50% reduction from baseline in ANDT counts at each scheduled evaluation time point The method of any one of claims 1 to 23, wherein one or more of the following is achieved:

25. 25. A method for preventing recurrence of HS in a patient treated with one or more parenteral doses of the anti-IL-36R antibody of any one of claims 1 to 24, comprising: administering to the patient one or more intravenous or subcutaneous doses of a prophylactically effective amount of an anti-IL-36R antibody. method.

26. 25. A method of achieving a Hidradenitis Suppurativa Clinical Response (HiSCR50) in patients treated with one or more parenteral doses of the anti-IL-36R antibody of any one of claims 1 to 24, comprising: administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous or subcutaneous doses. method.

27. 25. A method of achieving complete resolution of HS symptoms in a patient treated with one or more parenteral doses of an anti-IL-36R antibody according to any one of claims 1 to 24, comprising: administering to the patient one or more intravenous or subcutaneous doses of an effective amount of an anti-IL-36R antibody, wherein the HS symptoms include inflammatory lesions, abscesses, draining tracts / fistulas or draining ducts (dT), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection, and / or HS-associated pain; method.

28. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients achieve a clinical response as measured by the Hidradenitis Suppurativa Clinical Response Score (HiSCR), defined as at least a 50% reduction from baseline in total AN counts without an increase in the number of abscesses or draining fistulas at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

29. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show significant clinical improvement as measured by % change from baseline in total AN counts at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

30. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show a significant clinical improvement in HS flare incidence (flare incidence defined as at least a 25% increase in AN counts accompanied by a maximum of a 2 increase over baseline in total AN counts) at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

31. 28. The method of any one of claims 25 to 27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show significant clinical improvement as measured by change in % change from baseline in total dT counts at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

32. 28. The method of any one of claims 25 to 27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients exhibit complete loss of dT at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

33. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show significant clinical improvement as measured by absolute change from baseline in the International Hidradenitis Suppurativa Severity Scoring System (IHS4) at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

34. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show significant clinical improvement as measured by absolute change from baseline in Hidradenitis Suppurativa Area-Severity Index (HASI) at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

35. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients exhibit a 30% reduction from baseline in the Numeric Rating Scale for Patient Global Assessment of HS Pain (NRS30) at 8, 12, 16, 20, 24, 36, 48, 52, 60, or 72 weeks of treatment.

36. 28. The method of any one of claims 25 to 27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients exhibit a score of 0 or 1 as measured by Physician Global Assessment (PGA) at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

37. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show clinical improvement as measured by absolute change from baseline in Dermatology Life Quality Index (DLQI) score at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

38. 28. The method of any one of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients show clinical improvement as measured by absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at 8, 12, 16, 20, 24, 36, 48, 52, 60 or 72 weeks of treatment.

39. 1. A method of treating HS in a patient, comprising: administering to said patient one or more intravenous or subcutaneous doses of a therapeutically effective amount of an anti-IL-36R antibody of any one of claims 1 to 38, followed by one or more subcutaneous doses of an anti-IL-36R antibody. method.

40. 40. The method of claim 39, wherein 1, 2, 3, or 4 intravenous doses of the anti-IL-36R antibody are administered followed by 1, 2, 3, or 4 subcutaneous doses of the anti-IL-36R antibody.

41. 41. The method of claim 39 or 40, wherein the one or more intravenous or subcutaneous doses comprise 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, or 3000 mg of anti-IL-36R antibody, respectively, and the one or more subcutaneous doses comprise 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg of anti-IL-36R antibody, respectively.

42. 1. A method of treating HS in a patient, comprising: a. obtaining a biological sample from the patient, wherein the biological sample is obtained from a source including lesional skin or whole blood; b. determining a gene expression profile of one or more genes; c. administering to said patient an effective amount of the anti-IL-36R antibody of any one of claims 1 to 41. method.

43. 43. The method of claim 42, wherein the one or more genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24 or IL1B in lesional skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9 or CD177 in whole blood.

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