Use of anti-IL-36R antibodies for treatment of hidradenitis suppurativa (HS)

Abstract

The present invention provides methods, uses and compositions for the treatment of hidradenitis suppurativa. The present invention describes methods and uses for the treatment of hidradenitis suppurativa with an anti-interleukin 36R (anti-IL36R) antibody. Methods for determining the efficacy of an anti-IL36R antibody to treat hidradenitis suppurativa in a subject are also described.

Description

SEQUENCE LISTING

[0001] This application contains a Sequence Listing which has been submitted in XML format and which is hereby incorporated by reference in its entirety. The XML copy, created on March 1, 2024, is named 09-0743-WO-1_SL.xml and is 135,435 bytes in size. TECHNICAL FIELD

[0002] The present invention relates to the administration of an anti-Interleukin-36 Receptor (anti-IL-36R) antibody to an individual having hidradenitis suppurativa (HS) and the treatment and / or prevention of hidradenitis suppurativa (HS) in an individual. More particularly, the present invention relates to the administration of spesolimab to an individual having hidradenitis suppurativa (HS). BACKGROUND

[0003] Hidradenitis suppurativa (HS), also known as acne inversa, is a rare, chronic inflammatory skin disease characterized by recurrent, painful abscesses and draining tunnels. HS patients are objectively among the lowest quality of life measures of any skin disease. Lesions typically occur in the underarms, groin, submammary, or anal and genital regions of the body. HS lesions can progress to form sinus tracts and expanding abscesses. Sequelae include significant pain, scarring, and psychological distress. The mean 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% in total, ranging from 0.2% to 0.6%, with differences between different geographical settings. (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 misdiagnosis is common. Overall, HS incidence varies significantly based on study methodology; however, the disease appears 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] From a patient perspective, some of the most severe HS symptoms are pain, draining and bursting lesions, itching, skin tautness (cicatrization), odor, fatigue, and flu-like symptoms. Patients report dissatisfaction with the degree of control provided by current available treatment options; unmet needs from a patient perspective include the need for new medical treatments with a good efficacy and tolerability profile. In qualitative evidence, the most important treatment goals from a patient perspective were pain, draining (including bursting lesions), and fatigue.

[0006] Autoinflammation is proposed to play a role in the pathogenesis. Although abnormal levels of several inflammatory cytokines have been observed, the exact cytokine profile of HS remains to be determined. Protein levels of TNFa are also elevated in these patients.

[0007] The genetic basis of HS has been identified in some families with a history of HS. The earliest mutations identified in families with HS were in gamma-secretase, an endoprotease complex that cleaves a variety of type 1 transmembrane proteins and is encoded by several genes, including NCSTN, PSENEN, and PSEN1. Loss-of-function mutations within the NCSTN gene, which encodes one of the four subunits of gamma-secretase 68, support a key role for the gamma-secretase complex in HS. Despite a lack of robust correlation between genotype and phenotype, the clinical phenotype observed in NCSTN mutation-positive patients with HS is severe and widespread.In most patients, HS is triggered by environmental factors in people with a genetic predisposition (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 gamma-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 usually starts with topical or oral antibiotics, such as topical clindamycin and oral tetracycline, followed by rifampicin if there is no improvement. When topical medications and oral antibiotics are ineffective or the disease has progressed, the use of biologies is 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). Although the TNF-a antagonist Adalimumab is the only approved biologic, its response rate is 42% to 59% versus 26% to 28% for placebo, with a schedule of qlw subcutaneous administration. Biologics are an emerging treatment modality for managing a variety of inflammatory conditions including HS. Implementation of biologics is generally reserved for moderate to severe cases or in those cases that are refractory to treatment. Despite, recent results with drugs targeting the IL-17 pathway, bimekizumab and brodalumab, have shown real promise, other biologic agents including (for example) Infliximab (anti-TNF-a, an open-label phase II study with 17 patients), Golimumab (anti-TNF-a, no clinical studies, only case reports), Enteracept (soluble TNF receptor, double-blind study), Ustekinumab (anti-IL-12 / IL-23, an open-label phase II study with 17 patients), Guselkumab (anti-IL-23, phase II), Risankizumab (anti-IL-23, phase II), Anakinra (anti-ILl a, an open-label phase II study with 17 patients), Bermekimab (anti-ILl a, a double-blind randomized clinical trial (RCT) including 20 patients, an open-label clinical trial including 6 patients), Secukinumab (anti-IL-17, clinical trials ongoing), Bimekizumab (anti-IL-17A / F, phase III trial met primary endpoints showing statistically significant and consistent clinically meaningful improvements), Brodalumab (anti-IL-17R, phase II ongoing) have limited testing results (Flood KS, Porter ML, Kimball AB. Biologic Treatment for Hidradenitis Suppurativa. Am J Clin Dermatol. 2019 Oct; 20(5): 625-638; Glatt S, Jemec GB E, 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). Surgery is the only option when medical management fails.

[0009] The relationship between IL-36 and the pathogenesis of HS has also been investigated. However, in a recent clinical trial of an anti-IL36 R antagonist (imsidolimab) for the treatment of moderate to severe hidradenitis suppurativa (HS), there was no significant improvement in the primary and key secondary endpoints of HS compared to placebo (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 novel targeted therapies for the treatment and / or prevention of hidradenitis suppurativa (HS). SUMMARY

[0011] In view of the limited success achieved in the treatment of hidradenitis suppurativa (HS), especially in view of the debilitating nature of this disease, there remains a need for effective treatments. The present invention addresses the above need by providing a biologic therapeutic, particularly an antibody, that binds to IL-36R as a first-, second-, third- or subsequent line therapy 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 an individual comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen binding fragment thereof. In one embodiment related to this aspect, the anti-IL-36R antibody is bimekizumab.

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

[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 or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody or antigen binding fragment thereof of the present invention. In one embodiment related to this aspect, the anti-IL-36R antibody is bimekizumab.

[0015] In a fourth aspect, the present invention relates to a method of reducing or alleviating signs and symptoms of HS in a patient comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody. In one embodiment related to this aspect, the present invention is a method of reducing or alleviating the number, incidence, severity and / or recurrence of draining tubes in a patient with HS comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody. In one embodiment related to this aspect, the anti-IL-36R antibody is bimekizumab.

[0016] In a fifth aspect, the present application relates to a method of treating skin inflammation associated with hidradenitis suppurativa (HS) in an individual, comprising administering or having administered to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present application. In one embodiment relating to this aspect, the anti-IL-36R antibody is pexelizumab. In a related embodiment, the present application relates to a method of preventing or reducing neutrophil infiltration in diseased skin tissue of an individual having hidradenitis suppurativa (HS), comprising administering or having administered to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof of the present application. In one embodiment relating to this aspect, the anti-IL-36R antibody is pexelizumab. In one embodiment relating to this aspect, the present application relates to a method of reducing susceptibility to skin infection in an individual having hidradenitis suppurativa (HS), comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof (as disclosed herein). In one embodiment relating to this aspect, the anti-IL-36R antibody is pexelizumab.

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

[0018] In one embodiment relating to any of the first through sixth aspects, a second therapeutic agent is administered to the individual prior to, after, or concurrently with the anti-IL-36R antibody or antigen-binding fragment thereof. In a related embodiment, 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-alpha inhibitor, and an IFNgamma.

[0019] In one embodiment related to any of the first through sixth aspects, the anti-IL-36R antibody comprises: a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53 or 141; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72.

[0020] In one embodiment related to any of the first through sixth aspects, the anti-IL-36R antibody comprises: a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 141; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72.

[0021] In one embodiment related to any of the first through sixth aspects, the anti-IL-36R antibody comprises: i. a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 102; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or ii. a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 103; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iii. a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 104; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iv. a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 105; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or v. a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 106; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or vi. a light chain variable region comprising the amino acid sequence of SEQ ID NO:26 (L-CDR1); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 140 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); a heavy chain variable region comprising 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); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 104 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62, 108, 109, 110, 111, or 142 (H-CDR2); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:72 (H-CDR3).

[0022] In one embodiment related to any of the first through sixth 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.

[0023] In one embodiment related to any of the first through sixth aspects, the anti-IL-36R antibody 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.

[0024] In one embodiment related to any of the first through sixth aspects, the application provides a method for treating an individual having hidradenitis suppurativa (HS), the method comprising administering to the individual an isolated human anti-IL-36R antibody, or antigen-binding portion thereof, according to a plurality of variable dosage regimens, such that HS is treated, wherein the plurality of variable dosage regimens comprises administering at least one or more parenteral (e.g., intravenous or subcutaneous) doses. In a related embodiment, each of the one or more parenteral doses comprises at least 450 mg, 600 mg, 900 mg, 1200 mg, or 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 comprising at least 1800 mg of the anti-IL-36R antibody of one or more parenteral doses of 450 mg, 600 mg, 900 mg, 1200 mg, or 1800 mg. In a related embodiment, the anti-IL-36R antibody is administered at an effective dose as one, two, three, or four parenteral doses of (qw, q2w, q4w) 450 mg; one, two, three, or four parenteral doses of (qw, q2w, q4w) 600 mg; one, two, three, or four parenteral doses of (qw, q2w, q4w) 900 mg; one, two, three, or four parenteral doses of (qw, q2w, q4w) 1200 mg; one, two, three, or four parenteral doses of (qw, q2w, q4w) 1800 mg, one, two, three, or four parenteral doses of (qw, q2w, q4w) 2000 mg; one or two parenteral doses of (q2w, q4w) 2400 mg; one or two parenteral doses of (q2w, q4w) 3000 mg; or any combination thereof. In a related embodiment, the 1, 2, 3, or 4 parenteral doses are administered at 1 (qw), 2 (q2w), or 4 week (q4w) intervals.

[0025] In one embodiment related to any of the first through sixth aspects, the application provides a method for treating a subject having hidradenitis suppurativa (HS), the method comprising administering to the subject an isolated human anti-IL-36R antibody, or antigen binding portion thereof, according to a plurality of variable dosage regimens, such that HS is treated, wherein the plurality of variable dosage regimens 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, 600 mg, 900 mg, 1200 mg, or 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 comprising one or more intravenous doses of 450 mg, 600 mg, 900 mg, 1200 mg, or 1800 mg of the anti-IL-36R antibody. In a related embodiment, the anti-IL-36R antibody is administered at an effective dose as one, two, three, or four intravenous doses of (qw, q2w, q4w) 450 mg; one, two, three, or four non-parenteral doses of 600 mg (qw, q2w, q4w); one, two, three, or four intravenous doses of (qw, q2w, q4w) 900 mg; one, two, three, or four intravenous doses of (qw, q2w, q4w) 1200 mg; one, two, three, or four intravenous doses of (qw, q2w, q4w) 1800 mg, one, two, three, or four intravenous doses of (qw, q2w, q4w) 2000 mg; one or two intravenous doses of (q2w, q4w) 2400 mg; one or two intravenous doses of (q2w, q4w) 3000 mg, or any combination thereof.

[0026] In one embodiment related to any of the first through sixth aspects, the application provides a method for treating an individual having hidradenitis suppurativa (HS), the method comprising administering to the individual an isolated human anti-IL-36R antibody, or antigen-binding portion thereof, according to a plurality of variable dose regimens, such that HS is treated, wherein the plurality of variable dose regimens comprises administration of 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 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 comprising one or more subcutaneous doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 2000 mg of the anti-IL-36R antibody. In a related embodiment, the anti-IL-36R antibody is administered at an effective dose as one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 450 mg; one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 600 mg; one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 900 mg; one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 1200 mg; one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 1800 mg, one, two, three, or four subcutaneous doses of (qw, q2w, q4w) 2000 mg; one or two subcutaneous doses of (qw, q2w, q4w) 2400 mg; one or two subcutaneous doses of (qw, q2w, q4w) 3000 mg, or any combination thereof. In a related embodiment, the 1, 2, 3, or 4 subcutaneous doses are administered at 1 (qw), 2 (q2w), or 4-week (q4w) intervals.

[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 doses 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 non-limiting exemplary embodiments, 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, and 2, 3 for a total loading dose of 3600 mg; or four intravenous doses of 1800 mg are delivered at weeks 0, 1, and 2, 3 for a total loading dose of 7200 mg.

[0028] Table 1: Exemplary loading doses:

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

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

[0031] In another embodiment related to any of the first through sixth aspects, the present application comprises administering or having administered to the individual an isolated human anti-IL-36R antibody or antigen-binding portion thereof according to a plurality of variable dosing regimens, wherein the plurality of variable dosing regimens comprises administering a loading dose comprising at least 1, 2, 3, 4 intravenous doses or subcutaneous doses of 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400 mg, 3000 mg 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 individual at 1, 2, or 4 week intervals (qw, q2w, q4w) from week 4 after the loading dose of intravenous doses.

[0032] In one embodiment related to any of the above aspects and embodiments, the anti-IL-36R antibody is administered at a maintenance dose from week 4 with one or more intravenous or subcutaneous doses, 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, one, two, three, or four subcutaneous doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, 3000 mg, or any combination thereof every 1, 2, or 4 weeks (qw, q2w, q4w) is delivered at week 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0033] 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, 2400 mg, 3000 mg, 3600 mg, 4800 mg, 6000 mg, 7200 mg, or 8000 mg for the first 4 weeks, followed by one, two, three, four, five, or six subcutaneous maintenance doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, or combinations thereof, delivered every 1, 2, or 4 weeks (qw, q2w, q4w) at weeks 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In a preferred embodiment, the maintenance doses are delivered as four subcutaneous doses of 300, 450, 600, 900 mg, 1200 mg, delivered every week (qw) between weeks 4 and 8, for a total maintenance dose of 1200 mg, 1800 mg, 2400 mg, 3600 mg, or 4800 mg. In an alternative embodiment, the maintenance doses are delivered as two subcutaneous doses of 2400 mg or 3000 mg, delivered every two weeks between weeks 4 and 8, for a total maintenance dose of 4800 mg or 6000 mg. In an alternative embodiment, the maintenance doses are delivered as a total subcutaneous dose of 4800 mg or 6000 mg once, delivered between weeks 4 and 8, for a total maintenance dose of 4800 mg or 6000 mg.

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

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

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

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

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

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

[0040] In one embodiment related to any of the above aspects and embodiments, the anti-IL-36R antibody is administered in one or more intravenous doses 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 every week, for example, at weeks 4, 5, 6, and 7. In non-limiting exemplary embodiments, four subcutaneous doses of 300 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 1200 mg; four subcutaneous doses of 600 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 2400 mg; or four subcutaneous doses of 1200 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 3600 mg. In a related embodiment, at least one maintenance dose is administered after the final dose comprising the loading dose.

[0041] Table 2: Exemplary maintenance dosing weeks 4-8:

[0042] In one embodiment related to any of the above aspects and embodiments, the anti-IL-36R antibody maintenance therapy can continue after week 8 comprising at least one subcutaneous dose, wherein the subcutaneous dosing remains the same, or can be titrated up or down, and wherein each dose is 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, given every 2 (q2w) or 4 (q4w) weeks after week 8 after the last subcutaneous maintenance dose (e.g., between weeks 4 and 8). In a non-limiting exemplary embodiment, four subcutaneous doses of 300 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 1200 mg, followed by at least one 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg subcutaneous dose given preferably every two weeks (q2w) between weeks 8 and 52. In an alternative embodiment, four subcutaneous doses of 600 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 2400 mg, followed by at least one 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg subcutaneous dose given preferably every two weeks (q2w) between weeks 8 and 52. In yet another alternative embodiment, four subcutaneous doses of 1200 mg are delivered once a week at weeks 4, 5, 6, and 7 for a total maintenance dose of 3600 mg, followed by at least one 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg subcutaneous dose given preferably every two weeks (q2w) between weeks 8 and 52.

[0043] Table 3: Exemplary maintenance therapy > week 8 - week 52:

[0044] In another embodiment related to the above embodiments or first through sixth aspects, administration results in one or more of the following efficacy assessment indicators: (a) Percent 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 Score System (IHS4) value at week 12 (d) Absolute change from baseline in Hidradenitis Suppurativa Area and Severity Index (HASI) score at week 12 (e) Achievement of at least 30% reduction from baseline in patient's Numerical Rating Scale (NRS30) assessment of overall pain from HS at week 12 (f) achieving a Physician's Global Assessment (PGA) score of 0 or 1 at Week 12 (g) achieving complete resolution of dTs at Week 12 (h) achieving at least one flare (defined as at least a 25% increase in AN count from baseline up to Week 12, with a minimum increase of 2. (i) absolute change in Dermatology Life Quality Index (DLQI) score from baseline at Week 12. (j) absolute change in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score from baseline at Week 12.

[0045] In another embodiment related to the above embodiments or first through sixth aspects, administration results in one or more of the following efficacy assessment indicators: (a) percent change in dT count from baseline at Week 8 and / or Week 16; (b) absolute change in IHS4 value from baseline at Week 8 and / or Week 16; (c) absolute change in Hidradenitis Suppurativa Area Severity Index (HASI) score from baseline at Week 16; (d) achieving Hidradenitis Suppurativa Clinical Response (HiSCR50) at Week 16; (e) percent change in abscess count from baseline at Week 16; (f) achieving at least a 50% reduction in dT count from baseline at Week 16; (g) achieving at least a 50% reduction in abscess and dT (AdT) count from baseline at Week 16; (h) achieving at least a 50% reduction in AN dT count from baseline at Week 16; (i) achieving at least a 30% reduction in Numerical Rating Scale (NRS30) of patient's global assessment of HS pain from baseline at Week 16; (j) percent change in dT count from baseline at each scheduled assessment; (k) achieving at least a 50% reduction in dT count from baseline at each scheduled assessment; (l) achieving complete resolution of dTs at each scheduled assessment; (m) time to first occurrence of complete resolution of dTs during the treatment period; (n) percent change in abscess count from baseline at each scheduled assessment; (o) achieving at least a 50% reduction in abscess count from baseline at each scheduled assessment; (p) achieving complete resolution of abscesses at each scheduled assessment; (q) the percent change from baseline in total AdT count at each scheduled assessment; (r) at least a 50% reduction from baseline in the AdT count achieved at each scheduled assessment; (s) the percent change from baseline in inflammatory nodules (N) count at each scheduled assessment; (t) at least a 30% reduction from baseline in the numerical rating scale (NRS30) of patients' global assessment of HS pain at each scheduled assessment; (u) the absolute change from baseline in hidradenitis suppurativa quality of life (HiS-QoL) total score at each scheduled assessment; (v) the absolute change from baseline in FACIT-Fatigue scale score at each scheduled assessment; (w) the absolute change from baseline in Dermatology Life Quality Index (DLQI) score at each scheduled assessment; (x) the absolute change from baseline in Patient Change Global Impression (PGI-C) score over time; (y) the absolute change from baseline in Patient Severity Global Impression (PGI-S) score over time; (z) the change from baseline in hidradenitis suppurativa odor and discharge scale (HODS) at each scheduled assessment; (aa) the change from baseline in NRS pruritic disease at each scheduled assessment; (bb) the change from baseline in Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment; (cc) the percent change from baseline in total ANdT count at each scheduled assessment; or (dd) at least a 50% reduction from baseline in the ANdT count achieved at each scheduled assessment.

[0046] In another embodiment related to the above embodiments or first to sixth aspects, the proportion of individuals who respond to the administration is statistically significantly higher for one or more of the assessment indicators (a)-(j) and / or (a)-(dd) compared to individuals using a placebo.

[0047] In a seventh aspect, the present application relates to a method of treating or preventing a relapse of symptoms of HS in a patient treated with a non-parenteral dose of one or more anti-IL-36R antibodies according to any of the preceding aspects and embodiments, the method comprising administering to the patient a therapeutically or prophylactically effective amount of the anti-IL-36R antibody in one or more intravenous or subcutaneous doses.

[0048] In an eighth aspect, the present application relates to a method of achieving a score of a clinical response of hidradenitis suppurativa (HiSCR50) in a patient treated with one or more parenteral doses of an anti-IL-36R antibody according to any of the preceding aspects and 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 present application relates to 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 of the preceding aspects and 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, wherein the HS symptoms comprise inflammatory lesions, abscesses, draining fistula / sinuses or ducts (dTs), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection, and / or HS-associated pain.

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

[0051] In an eleventh embodiment, the present application provides a method of treating certain subpopulations of individuals, including, for example, individuals for whom previous therapy has failed or who have had a suboptimal response as a secondary therapy, including, for example, individuals who have had an inadequate response to or are intolerant of or have a contraindication to oral antibiotics. In certain embodiments, the present application is used to treat HS in individuals who have had an inadequate response to or are intolerant of oral antibiotics for the treatment of their hidradenitis suppurativa, or individuals who have had an inadequate response to or are intolerant of or have a contraindication to TNF-a inhibitors. In certain embodiments, the present application is used to treat HS in individuals who have had an inadequate response to or are intolerant of TNF-a for the treatment of their hidradenitis suppurativa.

[0052] In a twelfth embodiment, the present application includes treating individuals who have an AN count of greater than or equal to 1 at baseline, greater than or equal to 2 at baseline, greater than or equal to 3 at baseline, greater than or equal to 4 at baseline, or greater than or equal to 5 at baseline.

[0053] In another embodiment related to embodiments or aspects nine through twelve above, the present application provides a method for reducing the number of inflammatory lesions (AN count) or achieving hidradenitis suppurativa clinical response (HiSCR) in an individual having HS, the method comprising systemically administering to the individual an isolated human anti-IL36R antibody, or antigen binding portion thereof, such that the AN count is reduced. Clinical response according to the HiSCR scoring system is defined as at least a 50% reduction in total AN count from baseline, and no increase in abscess or draining fistula count.

[0054] In another embodiment related to embodiments or aspects nine through twelve above, after administration of the anti-IL36R antibody, or antigen binding portion thereof, the individual has no increase in abscess count and / or no increase in draining fistula or duct (dT) count.

[0055] In another embodiment related to embodiments or aspects ten through twelve above, the present application provides a reduction in the severity of HS according to IHS4 value, which is an absolute change from baseline in the assessment of HS severity according to the International Hidradenitis Suppurativa Severity Score (IHS4). Determination of IHS4 requires counting of nodules, abscesses, and draining fistula / sinus tracts. The absolute change from baseline or "IHS4" score assesses the severity of HS and the resulting IHS4 score is achieved by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tubes (multiplied by 4). A total score of 3 or less indicates mild, 4-10 indicates moderate, and 11 or higher indicates severe disease.

[0056] In another embodiment related to the above embodiments or aspects ten through twelve, the present application provides a method for improving (or reducing) the severity of HS as measured by the severity of HS symptoms from a higher score (e.g., HASI score of 3 or greater in one or more areas) to a no or low impact score (e.g., HS-PGA score of 0-2) in the area of Hidradenitis Suppurativa Area and Severity Index (HASI) score in a subject having Hidradenitis Suppurativa, comprising administering to the subject an IL-36R inhibitor (e.g., a human IL-36R antibody or antigen binding portion thereof) such that the HASI score is improved from a high score to a no or low impact score. The HASI score model is modeled after the Psoriasis Activity and Severity Index (PASI). Four cardinal signs of HS-related inflammation are included (erythema, induration, open ulcer, and draining tract). Each variable of the HASI for each predetermined body region is scored on a Likert scale (0-3). For BSA assessment, the number of palms involved for each body region (head, right axilla, left axilla, anterior chest, back, anterior bathing trunk, posterior bathing trunk, other) is assessed (one palm indicates 1% of the patient's BSA). This is converted to a percentage of the area. The area score is assigned to each region using the PASI method (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 4 clinical variable scores is multiplied by the area score for each involved region. This value is then multiplied by the proportion of the BSA of that region to give the local HASI score. The local HASI scores are added together to give the cumulative total HASI score (range 0-72). "HASI" combines the assessment of lesion severity and the area affected into a single score ranging from 0 (no disease) to 72 (severe disease).

[0057] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving (i.e., reducing) the Physician's Global Assessment of Hidradenitis Suppurativa (HS-PGA) score. The present application also provides a method of reducing the HS PGA score in a subject having hidradenitis suppurativa by at least about 2 grades, comprising administering an IL36R inhibitor, e.g., a human IL36R antibody or antigen-binding fragment thereof. The HS-PGA document is a physician's assessment of a patient's HS at a specified time point. It scores the patient's disease severity as clear, minimal, mild, moderate to severe, or very severe based on 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, where 0 (clear: no abscesses, draining tubes, inflammatory nodules, or non-inflammatory nodules), 1 (minimal: no abscesses, draining tubes, or inflammatory nodules and presence of non-inflammatory nodules), 2 (mild: no abscesses or draining tubes and 1-4 inflammatory nodules or 1 abscess or draining tube and no inflammatory nodules), 3 (moderate: no abscesses or draining tubes and >5 inflammatory nodules or 1 abscess or draining tube and >1 inflammatory nodule or 2-5 abscesses or draining tubes and <10 inflammatory nodules), 4 (severe: 2-5 abscesses or draining tubes and >10 inflammatory nodules), 5 (very severe: >5 abscesses or draining tubes).

[0058] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of reducing the HS-PGA score in a subject having hidradenitis suppurativa from a higher score (e.g., 3 or higher) to a no or low impact score (e.g., 0 to 2), comprising administering to the subject a human IL-36R antibody, such that the HS-PGA score is reduced from the higher score to the no or low impact score.

[0059] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of reducing the HS-PGA score in a subject having hidradenitis suppurativa by at least about 2 grades, comprising administering to the subject a human IL-36R antibody, such that the HS-PGA score is reduced by at least about 2 grades.

[0060] In another embodiment related to any of the above embodiments or aspects ten through twelve, the numerical rating scale (NRS30) of the patient's global assessment of Hidradenitis Suppurativa (HS) pain can also be used as an index to measure the effectiveness of an anti-IL36R antibody, or antigen-binding portion thereof, in a patient or population of patients having Hidradenitis Suppurativa, wherein a mean statistically significant (compared to placebo) improvement in the NRS30 pain score of at least 30% within the treated population of individuals is indicative of the IL-36R antibody being effective in treating Hidradenitis Suppurativa. The HS pain NRS is an assessment indicator used in clinical trials to assess the severity of HS-related pain in individuals with HS. Responses are given on an 11-point scale ranging from 0 (no HS pain) to 10 (HS pain is unimaginable). In related embodiments, the present application provides a method for determining whether a human IL-36R antibody is effective in treating Hidradenitis Suppurativa based on an improvement in the NRS30 pain score.

[0061] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving the Dermatology Life Quality Index (DLQI) score of an individual having Hidradenitis Suppurativa from a high score (i.e., impaired quality of life) to a low score (i.e., quality of life not or less affected), comprising administering to the individual a human IL-36R antibody such that the DLQI score is reduced from a high score to a low score. The DLQI is a quality of life questionnaire given to patients containing ten questions that cover six areas, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Joint Ann Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6-10 Jul 1993. Clin Exp Dermatol 1994; 19:210-216). The DLQI has a one-week recall period. Response categories include "not relevant" (score of 0), "not at all" (score of 0), "a little" (score of 1), "a lot" (score of 2), and "a great deal" (score of 3). Question 7 is a "yes" / "no" question, with a "yes" score of 3. The total DLQI score is calculated by summing the scores for each question resulting in a range of 0 to 30. The higher the score, the more impaired the quality of life.

[0062] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving the hidradenitis suppurativa quality of life (HiS-QoL) score of an individual having hidradenitis suppurativa from a high score (i.e., quality of life is highly affected) to a low score (i.e., low impact on quality of life), comprising administering to the individual a human IL-36R antibody such that the HiS-QoL score decreases from the high score to the low score. The HiS-QoL questionnaire is a 17-item instrument administered to patients to measure HS-specific quality of life in clinical trials. The 17 HiS-QoL includes four symptom items, eight activity accommodation items, and five psychosocial items. The items are summed to produce a total score ranging from 0 to 68, where a higher score indicates a more severe impact on quality of life.

[0063] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving the symptoms of HS or reducing the severity of pruritus associated with HS as scored according to the Numerical Rating Scale for Pruritus (NRS Pruritus), comprising administering to the individual a human IL-36R antibody such that the score decreases from the high baseline score to a low score. The HS Pruritus NRS is an assessment indicator used to assess the severity of HS-related pruritus in individuals with HS in clinical trials. Patient global assessment of HS pruritus assesses the worst HS pruritus. The rating ranges from 0 (no itch) to 10 (worst imaginable itch). It is a unidimensional measure of itch intensity and can be administered daily with minimal burden to the trial participant. The recall period is 24 h and the response is given by an 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). The trial participant is asked to rate their itch intensity using this scale.

[0064] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving the symptoms of HS or reducing the incidence of drainage and odor caused by clinical symptoms of HS according to the Hidradenitis Suppurativa Odor and Drainage Scale (HODS), comprising administering to the individual a human IL-36R antibody such that the score decreases from the high baseline score to a low score. The HODS is an 8-item scale developed to assess HS-related drainage and odor in individuals. It encompasses two areas: drainage (5 items) and odor (3 items). Response options range from 1 to 5. A higher score depicts a worse outcome of the concept assessed.

[0065] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of reducing and / or improving anxiety and / or depression in a subject having HS according to the Hospital Anxiety and Depression Scale (HADS), comprising administering to the subject a human IL-36R antibody such that the score is reduced from the high baseline score to a low score. The HADS is an instrument for screening for anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 for each of anxiety and depressive symptoms; the possible score range for the subscales is 0 to 21.

[0066] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of improving work productivity and / or total activity in a patient with HS according to the Work Productivity and Activity Impairment Questionnaire: HS (WPAI-HS), comprising administering to the subject a human IL-36R antibody such that the score is reduced from the high baseline score (high impact) to a low score (low impact). The WPAI-HS is a 6-item instrument to assess the impact of hidradenitis suppurativa on the ability to work and perform normal daily activities.

[0067] In another embodiment related to any of the above embodiments or aspects ten through twelve, the present application provides a method of reducing the impact 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 to the subject a human IL-36R antibody, wherein the improvement is a change from a high impact score to a low impact score. The described system comprises five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, assessing a pointer marking "best imaginable health" and "worst imaginable health."

[0068] In another embodiment related to any of the above embodiments or aspects ten through twelve, the proportion of individuals having a positive response to administration of an anti-IL36R antibody is statistically and / or significantly higher compared to individuals using a placebo for one or more assessment metrics. The assessment metrics can be a composite score of multiple scores using various assessment tools.

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

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

[0071] In a fifteenth aspect, the present application relates to a method of achieving improvement in one or more HS symptoms in a patient treated with one or more loading doses comprising an anti-IL-36R antibody according to any of the aspects or above embodiments, followed by one or more intravenous doses or subcutaneous doses of a maintenance dose; wherein the HS symptoms comprise inflammatory lesions, abscesses, draining fistula / sinuses or tunnels (dTs), HS-associated inflammation (erythema, induration, open ulcer), HS-associated infection, and / or HS-associated pain.

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

[0073] In one embodiment related to any of the above aspects or related embodiments thirteen to fifteen, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement as measured by percent change in total AN count from baseline at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0074] In one embodiment related to any of the above aspects or related embodiments thirteen to fifteen, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement as measured by percent change in total AN count from baseline at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

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

[0076] In one embodiment related to any of the above aspects or related embodiments thirteen to fifteen, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals achieve a clinical response measured by a Hidradenitis Suppurativa Clinical Response Score, HiSCR, defined by at least a 50% reduction in total AN count from baseline without an increase in abscess or draining fistula count at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

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

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

[0079] In one embodiment related to any of the above aspects or related embodiments thirteen to fifteen, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a 30% reduction from baseline in the Numerical Rating Scale (NRS30) of patient’s global assessment of HS pain at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

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

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

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

[0083] In one embodiment related to any of the above aspects or related embodiments thirteen to fifteen, the proportion of patients who respond to the administration is statistically significantly higher compared to individuals using a placebo for any of the recited indicators.

[0084] In another aspect, the application relates to 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 comprising lesional skin or whole blood;

[0085] (b) determining the gene expression profile of one or more of the genes;

[0086] (c) administering to the patient an effective amount of an anti-IL-36R antibody according to any embodiment related to any of the above aspects.

[0087] In one embodiment related to aspect tenth, one or more of the genes is 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.

[0088] It is to be understood that any of the methods, administration procedures, and / or dosing regimens disclosed herein are equally applicable to the use of any of the IL-36R antibodies disclosed in such methods, administration procedures, and / or dosing regimens: i.e., an anti-IL-36R antibody as disclosed herein for use in the treatment, prevention, and / or amelioration of any of the diseases and / or disorders disclosed. In other words, the present application also provides the use of an anti-IL-36R antibody as disclosed herein for the manufacture of a medicament for the treatment, prevention, reduction, and / or amelioration of any of the diseases and / or disorders disclosed.

[0089] Additional features and advantages of the present application will be apparent from the detailed description of the following embodiments, which proceeds with reference to the accompanying drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only, and are intended to provide further explanation of the present application as claimed. BRIEF DESCRIPTION OF DRAWINGS

[0090] The accompanying drawings are included to provide a further understanding of the present application and are incorporated in and constitute a part of this specification, illustrate aspects of the present application and together with the description serve to explain the principles of the present application.

[0091] Figure 1 IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) that inhibit the signaling cascade are shown.

[0092] Figure 2 IL-36 ligand expression by in situ hybridization (ISH) technique in human skin sections is shown. Formalin-fixed paraffin-embedded (FFPE) skin sections from HS lesional and non-lesional HS samples were purchased from a supplier and stained for IL-36a, b, g using ISH probes. Increased expression of all three IL36 ligands a, b, g was seen in HS skin samples.

[0093] Figures 3A-3BA. Phase IIa clinical study design: The clinical proof-of-concept was designed to explore the effect of pesonalimab in individuals with moderate to severe HS. Individuals who met the inclusion criteria also had HS lesions in > 2 different body regions; total abscess and inflammatory nodule (AN) count > 5; total draining tube count < 20; had not received biologic therapy or had failed prior TNFi therapy for HS, and had an inadequate response to oral antibiotics for HS in the past year. HS disease worsening was defined as an increase of 150% in AN count from baseline; during the course of the study, rescue monotherapy with doxycycline 100 mg was given orally twice daily, or an alternative regimen could be given for up to 2 weeks at the discretion of the investigator, and not more than a total of 4 weeks. 3B Baseline patient demographics: HS severity was based on the IHS4 criteria. AN, abscess and inflammatory nodule; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Severity Score System; i.v., intravenous; OLE, open-label extension; qw, once a week; q2w, every 2 weeks; SC, subcutaneous; SD, standard deviation. TNFi, TNF inhibitor.

[0094] Figure 4 Flow diagram of Phase IIa trial activity.

[0095] Figures 5A-5B A. LS mean percent change from baseline in total abscess and inflammatory nodule (AN) count: LS mean, difference, and confidence intervals were estimated by (REML)-based MMRM, including fixed categorical effects of treatment at each visit, prior use of TNF inhibitor strata, and continuous effects of baseline at each visit and random effects of individual. Analysis used data up to use of rescue therapy; data after use of rescue therapy was examined. Results were presented descriptively; individuals with non-missing values were included in the summary. B. Mean absolute change from baseline in lesion count at Week 12: the count of all types of HS inflammatory lesions tended to decrease after treatment with pesonalimab. AN, abscess and inflammatory nodule; dT, draining tube; LS, least squares; SD, standard deviation; SE, standard error.

[0096] Figures 6A-6BA. Percent change from baseline in dT counts at Week 12. A greater proportion of individuals in the pesonalizabt arm had a reduction in dTs from baseline at Week 12 compared to the placebo arm. 66.7% of individuals (16 / 24) in the pesonalizabt arm had a reduction in dTs from baseline at Week 12 compared to 38.5% of individuals (5 / 13) in the placebo arm. B. LS mean percent change from baseline in dT counts: LS mean, difference, and confidence intervals were estimated by a mixed-effects model repeated measures (MMRM) based on a restricted maximum likelihood (REML) that included a fixed categorical effect of treatment at each visit, a continuous effect of baseline at each visit, and a random effect of individual. Analyses used data up to use of rescue therapy; checks were performed on data after use of rescue therapy. dT, draining tube; LS, least squares; SE, standard error.

[0097] Figure 7 Safety profile of pesonalizabt: The safety profile was similar to previous trials; patients receiving pesonalizabt did not have serious adverse events. At Week 2, two individuals received a reversal therapy, so 36 individuals were exposed to pesonalizabt. Severe AEs were those with Grade 3 or 4 RCTC. According to ICH E3 guidelines. AE, adverse event; AESI, adverse event of special interest; AN, abscesses and inflammatory nodules; HS, hidradenitis suppurativa; N, nodules; RCTC, rheumatology common toxicity criteria.

[0098] Figures 8A-8B A. Phase IIa and OLE study design: At Week 24 (Week 12 of OLE), individuals could have their dose of pesonalizabt increased to 1200 mg SC q2w if necessary (based on responder status at the start of OLE and change in HS-PGA severity from the start of OLE); HS disease worsening was defined as an increase of 150% in abscesses and inflammatory nodules count from baseline; rescue monotherapy with systemic antibiotics or immunosuppressive biologies; §Baseline refers to the last measurement prior to starting brodalumab, i.e., the baseline of the Phase Ila trial in the prior brodalumab arm or the baseline of the OLE study in the prior placebo arm (IV, intravenous; OLE, open-label extension; q2w, every 2 weeks; R, randomized; SC, subcutaneous; SD, standard deviation)B. Patient characteristics at OLE baseline: Individuals who met inclusion criteria also had HS lesions in >2 distinct body regions; total abscess and inflammatory nodule (AN) count >5; total draining cord count <20; had not received biologic therapy or failed prior TNF-a inhibitor therapy for HS and had an inadequate response to oral antibiotic therapy for HS in the past year. (DLQI, Dermatology Life Quality Index; HASI, Hidradenitis Suppurativa Area and Severity Index; HiS-QOL, Hidradenitis Suppurativa Quality of Life; HS, hidradenitis suppurativa; HS-PGA, Hidradenitis Suppurativa Physician Global Assessment; IHS4, International Hidradenitis Suppurativa Severity Score)

[0099] Figures 9A-9D . Absolute change from baseline to Week 50 in lesion type and IHS4 score: 95% CI calculated based on Student's T distribution. Number of patients at baseline was prior brodalumab n=30 and prior placebo n=15. For change from baseline, only individuals with >1 relevant lesion type were included. Number of patients at Week 50 was prior brodalumab n=15 and prior placebo n=7. (All assessments after rescue medication were excluded). CI, confidence interval; IHS4, International Hidradenitis Suppurativa Severity Score). A. Mean (95% CI) absolute change from baseline in draining cord count. Prior brodalumab group = -1.3 (-2.9, 0.3); prior placebo group = -3.7 (0.3, -7.8) (includes individuals with >1 draining cord at baseline only). B. Mean (95% CI) absolute change from baseline in inflammatory nodule count. Prior brodalumab group = -3.7 (-7.9, 0.5); prior placebo group = -5.7 (-8.7, -2.8) (includes individuals with >1 inflammatory nodule at baseline only). C. Mean (95% CI) absolute change from baseline in abscess count. Prior brodalumab group = -0.9 (-2.2, 0.5); prior placebo group = -2.4 (-7.6, 2.8) (includes individuals with >1 abscess at baseline only). D. Mean (95% CI) absolute change from baseline in IHS4 score. Prior brodalumab group = -12.8 (-20.7, -5.0); prior placebo group = -23.4 (-50.8, 4.0).

[0100] Figures 10A-10BA. Part I (Phase IIb) trial design. A multicenter, double-blind, placebo-controlled, randomized trial that evaluates the efficacy and safety of pesotaximab relative to placebo in individuals with moderate to severe HS. B. Part 2 (Phase III) trial design: to be initiated after the primary analysis of Part 1 (Phase IIb), assessment of further development of benefit, interaction with HA, and approval by IRB / EC. (IC = informed consent, V = study visit, W = week (study week), FUP = follow-up, EoT = end of treatment, EoS = end of study, REP = residual effect period).

[0101] Figure 11A &11B. Flow chart of Phase IIb trial activities. A. Treatment period up to Week 32. B. Treatment period after Week 32, up to Week 48. EMBODIMENT

[0102] Before the application is described, it is to be understood that this application is not limited to the particular methodology and experimental conditions described, as such methodology and conditions can 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, as the scope of the application will be limited only by the appended claims.

[0103] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the application. However, it will be apparent to one skilled in the art that the application can be practiced without some or all of these specific details. In other instances, well known structures and

[0104] 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 application belongs.

[0105] The present inventors have surprisingly found inhibition of the interleukin-36 pathway, especially in HS individuals treated with higher loading doses of the anti- interleukin-36R (anti-IL-36R) monoclonal antibody of the present application. Resulting positive key indications of reactivity include: percent change from baseline in dT counts, absolute change from baseline in IHS4 (dT, abscess, and inflammatory weight counts), and absolute change from baseline in HASI (severity index of HS), as well as other clinical symptoms in individuals 12 weeks after administration.

[0106] In one aspect, the present application relates to a method for treating, preventing, or ameliorating hidradenitis suppurativa (HS) in an individual comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is pesotaximab.

[0107] Without wishing to be bound by this theory, it is believed that the anti-IL-36R antibodies or antigen-binding fragments thereof bind to human IL-36R and thus interfere with the binding of IL-36 agonists and, in this operation, at least partially block 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 the agonistic IL-36 ligands (a, b or g) initiate a signaling cascade by engaging the IL-36 receptor, which then forms a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP).

[0108] IL36R is a cell surface receptor involved in inflammatory responses in the skin and gut. It is a novel member of the IL1R family, forming a heterodimeric complex with the IL1R accessory protein. The heterodimeric IL36R system with stimulatory (IL36a, IL36b, IL36g) and inhibitory ligands (IL36Ra) shares multiple structural and functional similarities with other members of the IL1 / IL1R family, such as IL1, IL18, and IL33 (R17-3602). All IL1 family members (IL1a, IL1b, IL18, IL36a, IL36b, IL36g, and IL38) signal through unique cognate receptor proteins that, upon ligand binding, recruit the common IL1RacP subunit in receptor-positive cell types and activate the NFkB and MAP kinase pathways. In human skin tissue, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrating myeloid cells. IL36R activation in skin tissue drives the production of inflammatory mediators (e.g., CCL20, MIP-1b, TNF-a, IL12, IL17, IL23, TGF-b) and modulates the expression of tissue remodeling genes (e.g., MMPs, TGF-b).

[0109] Anti-IL36R antibodies of the present invention are disclosed herein, for example, in U.S. Patent No. 9,023,995, the entire contents of which are incorporated herein by reference.

[0110] Although any methods and materials described herein can be used in the practice of the present application, preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe in full. Definitions

[0111] phrases such as "one aspect" do not imply that the aspect is essential to the invention, or that the aspect applies to all configurations of the invention technology. A disclosure relating to an aspect can apply to all aspects or one or more aspects. An aspect can provide one or more embodiments of the invention. Phrases such as "one aspect" can refer to one or more aspects and vice versa. Phrases such as "one embodiment" do not imply that the embodiment is essential to the invention, or that the embodiment applies to all configurations of the invention technology. A disclosure relating to an embodiment can apply to all embodiments or one or more embodiments. An embodiment can provide one or more embodiments of the invention.

[0112] The term "about" shall generally mean an acceptable limit or degree of deviation or error in a measured quantity, given the nature or precision of the measurement. A typical exemplary degree of error is within 5% or within 3% or within 1% of a stated value or range of values. For example, the expression "about 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all values in between (e.g., for a range of 95 to 105, 95.1, 95.2, etc.; or for a range of 97 to 103, 97.1, 97.2, etc.; for a range of 99 to 101, 99.1, 99.2, etc.). Unless otherwise stated, numerical values given herein are approximations, meaning that the term "about" can be inferred when not expressly stated. Therapeutic uses of antibodies

[0113] The role of neutrophils in skin inflammation is increasingly understood. While clearly based on the genetics and the role of the IL-36 pathway that is inhibited by Rilonacept, it is recognized that the same pathway is involved in other similar neutrophilic dermatoses (NDs), which are a group of heterogeneous diseases with common features and overlapping pathophysiology. While the diseases are primarily associated with cutaneous expression attributed to neutrophil accumulation, involvement of additional tissues is also found. Our studies suggest that the IL-36 pathway plays an important role in driving disease expression in pustular neutrophilic dermatoses (NDs) such as hidradenitis suppurativa (HS). Thus, blocking the IL-36 pathway should be beneficial in skin inflammation of papules, nodules, and flares such as hidradenitis suppurativa (HS).

[0114] The present invention provides anti-IL-36R antibodies and pharmaceutical compositions comprising anti-IL-36R antibodies for use in reducing, mitigating, or blocking the IL-36 pathway useful in the treatment or prevention of hidradenitis suppurativa (HS) in an individual, preferably a human.

[0115] In one embodiment, the present application provides a pharmaceutical composition formulated in unit dosage form, wherein such single dosage form comprises at least 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2000 mg, 2400, or 3000 mg of the anti-IL-36R antibody. In a related embodiment, the unit dosage form is used to prepare a medicament for treating an individual having hidradenitis suppurativa (HS). In a related embodiment, the unit dosage form is a parenteral (e.g., intravenous or subcutaneous) dosage form.

[0116] In a related embodiment, the present application provides a pharmaceutical preparation (or "article of manufacture" described below) comprising 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.

[0117] In a related embodiment, the one, two, three, or four unit dosage forms (e.g., in a pharmaceutical preparation) are administered at 1 (qw), 2 (q2w), or 4 week (q4w) intervals. Preferably, when the unit dosage form comprises 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, or 2000 mg of the anti-IL-36R antibody, the one, two, three, or four unit dosage forms are administered at 1 (qw), 2 (q2w), or 4 week (q4w) intervals; when the unit dosage form comprises 2400 mg or 3000 mg of the anti-IL-36R antibody, the one or two unit dosage forms are administered at 2 (q2w) or 4 week (q4w) intervals; when the unit dosage form comprises 300 mg of the anti-IL-36R antibody, the one, two, three, or four unit dosage forms are administered at 1 (qw) or 2 week (q2w) intervals as a subcutaneous maintenance dose.

[0118] In one aspect, the present application relates to a method for treating, preventing or ameliorating hidradenitis suppurativa (HS) in an individual comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein). In one embodiment relating to this aspect, the anti-IL-36R antibody is brexanolone.

[0119] In one aspect, the present application relates to the use of an anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) in the manufacture of a medicament for treating, preventing or ameliorating hidradenitis suppurativa (HS). In one embodiment relating to this aspect, the anti-IL-36R antibody is brexanolone.

[0120] Preferably, the HS is moderate to severe HS. "Moderate to severe" HS can be determined based on International Hidradenitis Suppurativa Severity Score System (IHS4) guidelines, present in at least 1 year prior to the baseline visit, as determined by the investigator via participant visit and / or review of medical history; if IHS4 score is not available, based on documented Investigator Assessment, equivalent score based on scoring system as HS-PGA or Hurley is acceptable. More preferably, HS lesions are present in at least 2 different anatomic regions (e.g., right / left axillae, inguinal, inframammary, perineum). More preferably, the HS is biologic- naive, previously TNF inhibitor (TNFi) treated HS failure. More preferably, when the HS is biologic-naive, the individual has had an inadequate response to an adequate course of treatment with appropriate oral antibiotics for HS within the past 1 year, according to investigator judgment.

[0121] In one aspect, the present application relates to a method of treating a skin disorder associated with hidradenitis suppurativa (HS) in a patient comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) of the present application. In one embodiment relating to this aspect, the anti-IL-36R antibody is brexanolone.

[0122] In one aspect, the present application relates to a method of treating skin inflammation associated with hidradenitis suppurativa (HS) in an individual comprising administering or having administered to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) of the present application. In one embodiment relating to this aspect, the anti-IL-36R antibody is brexanolone.

[0123] In one aspect, the present application relates to a method of preventing or reducing neutrophilic infiltration in diseased skin tissue of an individual having hidradenitis suppurativa (HS), the method comprising administering or having administered to the individual a therapeutically effective amount of an anti-IL-36R antibody of the present application, or antigen binding fragment thereof. In one embodiment related to this aspect, the anti-IL-36R antibody is pexelizumab.

[0124] A long-standing suspicion exists that an infectious process is associated with HS (Hight 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, in one study, anaerobic bacteria (such as Prevotella and Porphyromonas), coagulase-negative staphylococci, and S. aureus were common microorganisms in HS lesions (Wark KJL, Cains GD. The Microbiome in Hidradenitis Suppurativa: A Review. Dermatol Ther (Heidelb). 2021 Feb; 11(1): 39-52).

[0125] The purulent microbial communities in individuals with hidradenitis suppurativa were also studied and five microbial community types were identified overall: Porphyromonas (type I), Corynebacterium (type II), Staphylococcus (type III), Prevotella (type IV), and Acinetobacter (type V). Porphyromonas (type I) and Prevotella (type IV) were the most common genera in the purulent discharge (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).

[0126] In one study, bacterial cultures detected anaerobes in 83% of HS lesions compared to 53% of control samples, with Streptococcus milleri group and actinomycetes combinations detected in 33% and 26% of cases, respectively. High-throughput sequencing identified 43 taxa associated with HS lesions. Two gram-negative anaerobic rod-shaped taxa, Prevotella and Porphyromonas, predominated, while the abundance of aerobic commensal bacteria was reduced. Rare taxa of the normal skin microbiota were associated with lesions, independent of HS gender, duration, and family history, body mass index, and location. Two major additional taxa, Fusobacterium and Microsomonas, were associated with HS clinical severity (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).

[0127] In Guet-Revillet, et al., 2014, researchers linked HS disease severity to two different microbial profiles associated with clinical classification of Legionnaires' disease according to the Hurley scale (Guet-Revillet, H., Coignard-Biehler, H., Jais, J., Quesne, G., Frapy, E., Poirée, S.... Join-Lambert, O. (2014). Bacterial Pathogens Associated with Hidradenitis Suppurativa, France. Emerging Infectious Diseases, 20(12), 1990-1998). Although there is no consensus on a classification system, the Hurley classification system is 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). Briefly, the Hurley system divides HS into three stages: Stage 1 : single or multiple abscesses without sinus tract formation or scarring, which is most common; Stage 2: recurrent abscesses with one or more sinus tracts and scarring widely separated by normal skin; and Stage 3: diffuse involvement of multiple sinus tracts with no intervening normal skin.

[0128] In Guet-Revillet, et al., 2014, researchers demonstrated that 2 specific microbial profiles neither corresponded to the normal skin microbiota nor to common skin pathogens (S. aureus and S. pyogenes), and were associated with HS lesions and disease severity. The first microbial profile, "Profile A", was characterized by pure or predominant cultures of S. hominis, mainly associated with Hurley stage 1 lesions (lower severity score). The second microbial profile, "Profile B", was represented by a mixed flora composed of strict anaerobic Gram-negative and Gram-positive bacteria, anaerobic actinomyces and S. milleri group streptococci. Various other bacteria such as S. aureus, coagulase-negative staphylococci, corynebacteria, enterobacteriaceae, propionibacteria and enterococci were less stable and less numerous in association with the mixed anaerobic flora, especially when lesions were sampled by swab. This profile was mainly associated with open suppurative lesions observed in Hurley stages 2 and 3, and also with 24% of Hurley stage 1 lesions.

[0129] In one aspect, the present application relates to a method of reducing microbial colonization of the skin of an individual having hidradenitis suppurativa (HS), comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof disclosed herein. In one embodiment related to this aspect, the colonization is to a microbe selected from the group consisting of Staphylococcus aureus, Streptococcus spp., Pseudomonas aeruginosa, Bacteroides spp., molluscum contagiosum virus, Herpes simplex virus, coxsackievirus, vaccinia virus, Candida albicans, Microsporum spp., Trichophyton spp., Penicillium spp., Cladosporium spp., Alternaria spp., and Aspergillus spp. In another embodiment related to this aspect, the microbe is Staphylococcus aureus (S. aureus). In another embodiment related to this aspect, the colonization of S. aureus is reduced by at least 10% or at least 20% relative to baseline following administration of an anti-IL-36R antibody or antigen-binding fragment thereof disclosed herein. In one embodiment related to this aspect, the anti-IL-36R antibody is anifrolumab.

[0130] In one aspect, the present application relates to a method of reducing the susceptibility of an individual having hidradenitis suppurativa (HS) to a skin infection, comprising administering to the individual a therapeutically effective amount of an anti-IL-36-R antibody or antigen-binding fragment thereof disclosed herein. In one embodiment related to this aspect, the skin infection is caused by a microbe selected from the group consisting of Staphylococcus aureus, Streptococcus spp., Pseudomonas aeruginosa, Bacteroides spp., Herpes simplex virus, molluscum contagiosum virus, coxsackievirus, vaccinia virus, Candida albicans, Microsporum spp., Trichophyton spp., Penicillium spp., Cladosporium spp., Alternaria spp., and Aspergillus spp. In another embodiment related to this aspect, the microbe is Staphylococcus aureus (S. aureus). In one embodiment related to this aspect, the anti-IL-36R antibody is anifrolumab.

[0131] In one embodiment related to any of the above aspects, a second therapeutic agent is administered to the individual prior to, after, or simultaneously with the anti-IL-36R antibody or antigen-binding fragment thereof. In a related embodiment, 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 IFNy.

[0132] In one embodiment related to any of the above aspects, the anti-IL-36R antibody comprises: a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53 or 141; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72.

[0133] In one embodiment related to any of the above aspects, the anti-IL-36R antibody comprises: a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 141; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72.

[0134] In one embodiment related to any of the above aspects, the anti-IL-36R antibody comprises: i. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 102; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or ii. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 103; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iii. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 104; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iv. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 105; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or v. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO:26 (L-CDR1); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); a heavy chain variable region comprising 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); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 140 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); a heavy chain variable region comprising 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); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 104 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62, 108, 109, 110, 111, or 142 (H-CDR2); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:72 (H-CDR3).

[0135] In one embodiment related to any 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.

[0136] In one embodiment related to any of the above aspects, the anti-IL-36R antibody 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.

[0137] In another embodiment related to any of the above aspects or embodiments described herein, the anti-IL-36R antibody is pesolizumab.

[0138] In another embodiment related to any of the above aspects or embodiments described herein, a second therapeutic agent is administered to the individual before, after, or simultaneously with the anti-IL-36R antibody.

[0139] In another embodiment related to 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 IFN-γ. Pharmaceutical composition

[0140] The antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for administration to individuals. The compounds of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier, diluent, and / or excipient in a single or multiple dose. The pharmaceutical composition for administration is designed to be suitable for the selected mode of administration, and when appropriate, a pharmaceutically acceptable diluent, carrier, and / or excipient, such as a dispersant, a buffer, a surfactant, a preservative, a cosolvent, an isotonic agent, a stabilizer, etc., is used. The composition is designed according to the conventional techniques in, for example, Remington, The Science and Practice of Pharmacy, 19th edition, Gennaro, ed., Mack Publishing Co., Easton, PA 1995, which provides an overview of formulation techniques generally known to practitioners.

[0141] Pharmaceutical compositions comprising the anti-IL-36R monoclonal antibodies of the present application can be administered to individuals having a neutrophilic dermatosis described herein using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0142] The route of administration of the antibodies of the present application can be oral, parenteral, inhalation or topical. Preferably, the antibodies of the present application can be incorporated into pharmaceutical compositions suitable for parenteral administration. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration. Peripheral systemic delivery by intravenous or intraperitoneal or subcutaneous injection or infusion is preferred. Vehicles suitable for such injections are known in the art.

[0143] Pharmaceutical compositions must typically be sterile and stable under the conditions of manufacture and storage, in the container provided, including, for example, sealed vials or syringes (e.g., containing unit dosage forms). Thus, after the formulation is made, the pharmaceutical composition is either sterile filtered or made microbiologically acceptable. Typical compositions for intravenous infusion can have a volume of fluid in the range of up to 250 ml to 1000 ml, such as sterile Ringer's solution, physiological saline, dextrose solution, and Hank's solution, and a therapeutically effective dosage (e.g., 1 mg / mL to 100 mg / mL or more) of the antibody concentration. Dosages can further vary depending on the type and severity of the disease. As is well known in the medical arts, dosages for any particular patient depend on many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. A typical dosage can be in the range of, for example, 0.001 to 1000 mg; however, doses below or above this exemplary range are envisaged, especially taking into account the aforementioned factors.

[0144] The term "dose" as used herein refers to the amount of anti-IL-36R antibody or antigen-binding portion thereof administered to an individual.

[0145] The term "administering" as used herein refers to the act of giving an anti-IL-36R antibody or antigen-binding portion thereof to achieve a therapeutic goal (e.g., treating hidradenitis suppurativa).

[0146] A "dosing regimen" describes the treatment schedule for an anti-IL-36R antibody or antigen-binding portion thereof, for example, the treatment schedule over an extended period or throughout the course of treatment, for example, administering a first dose of an anti-IL-36R antibody or antigen-binding portion thereof 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.

[0147] The term "multiple variable dosing" includes the administration of different doses of an anti-IL-36R antibody, or antigen-binding portion thereof, to an individual for therapeutic treatment. "Multiple variable dosing regimen" or "multiple variable dosing therapy" describes a treatment schedule that is based on the administration of different amounts of an anti-IL-36R antibody, or antigen-binding portion thereof, at different time points throughout the course of treatment.

[0148] As used herein, the terms "intravenous dose (iv)," "subcutaneous dose (sc)" refer to the route of administration of an anti-IL-36R antibody. A "loading dose" can be an intravenous dose or a subcutaneous dose given at the beginning of the treatment regimen (also referred to as a "baseline dose"); it can also be referred to as an initial dose or an induction dose. A "maintenance dose" is typically a subcutaneous dose given after the loading and / or baseline dose, which can also be referred to as a "follow-up dose." Both loading and maintenance intravenous and subcutaneous doses can contain the same amount of an anti-IL-36R antibody, or antigen-binding fragment thereof, but generally can differ from each other in terms of the amount of antibody administered or the frequency of administration. In one embodiment, the loading dose is equal to or greater than the maintenance dose. The "loading dose," which is interchangeably referred to as an initial dose or an induction dose, can be a single dose, or alternatively, a set of doses comprising a total loading dose. The "maintenance dose," which can also be referred to as a follow-up dose, can be a single dose, or alternatively, a set of doses administered.

[0149] In certain embodiments, the amount of anti-IL-36R antibody contained in the induction / initial / load and maintenance / follow-on doses differs from one another during the course of treatment. In certain embodiments, one or more initial / induction doses each comprise a first amount of antibody or antigen-binding fragment thereof, and one or more maintenance / follow-on doses each comprise a second amount of antibody or antigen-binding fragment thereof. In some embodiments, the first total load dose of antibody or fragment thereof is 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, or 5-fold the second or subsequent amount of antibody or antigen-binding fragment thereof. In certain embodiments, at the beginning of the treatment regimen, one or more (e.g., 1, 2, 3, 4, or 5 or more) initial doses are administered as “induction doses” or “loading doses,” followed by subsequent doses as “maintenance doses” or “treatment doses.” In one embodiment, the total loading or induction dose comprises 1800 mg, 2400 mg, 3600 mg, 4800 mg, 6000 mg, 7200 mg, or 8000 mg of 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 between D0 and 4 weeks, every 1, 2, or 4 weeks (qw, q2w, q4w). In one exemplary embodiment, after the loading dose, a maintenance dose or follow-on dose of 1200 mg, 1800 mg, 2400 mg, 3600 mg, 4800 mg, or 6000 mg is administered as at least one subcutaneous dose of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 2400 mg, or 3000 mg every 1 week, 2 weeks, or 4 weeks (qw, q2w, q4w) between week 4 and week 8. In another embodiment, the subcutaneous dose or maintenance or follow-on dose is administered at least one week after the last loading or induction dose.

[0150] As used herein, the term “treatment period” or “maintenance period” refers to a period of treatment comprising administration of an anti-IL-36R antibody or antigen-binding portion thereof to an individual to maintain a desired therapeutic effect, e.g., improvement of symptoms associated with hidradenitis suppurativa, and typically is a period of time beginning 4 weeks after the initial loading dose (administered between 0-4 weeks).

[0151] The term "maintenance dose" or "therapeutic dose" is the amount of anti-IL-36R antibody, or antigen-binding portion thereof, taken by an individual to maintain or continue a desired therapeutic effect. The maintenance dose can be a single dose or a set of doses. The maintenance dose is given during the treatment or maintenance phase of therapy. In one embodiment, the total maintenance dose is less than the induction dose, where each dose, when given consecutively, can be equal to one another. In one embodiment, the present application provides a total maintenance dose of at least 1200, 1800 mg, 2400 mg, 3600 mg, 4800 mg, or 6000 mg of anti-IL-36R antibody, or antigen-binding portion thereof, administered to an individual in one or more subcutaneous doses of 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg every 1 week, 2 weeks, or 4 weeks (qw, q2w, q4w). In one embodiment, the maintenance dose is given weekly or every other week, starting 1 or 2 weeks after the last loading dose. In one embodiment, the maintenance dose is given about 4 weeks after the initial loading dose. The maintenance dose can be up-titrated or down-titrated to achieve the desired therapeutic purpose. In a preferred embodiment, the maintenance dose is less than the loading dose and / or is less frequent.

[0152] The term "maintenance therapy" or "maintenance dosing regimen" refers to the treatment schedule for an individual or patient diagnosed with a condition / disease (e.g., hidradenitis suppurativa) to enable them to maintain their health in a specified state, e.g., to reduce the number of inflammatory lesions or to achieve a clinical response. In one embodiment, the maintenance therapy of the present application is used for an individual or patient diagnosed with a condition / disease (e.g., hidradenitis suppurativa) to enable them to maintain their health in a state free of symptoms or reduced symptoms associated with the disease. In one embodiment, the maintenance therapy of the present application is used for an individual or patient diagnosed with a condition / disease (e.g., hidradenitis suppurativa) to enable them to maintain their health in a state substantially free of symptoms associated with the disease. In one embodiment, the maintenance therapy of the present application is used for an individual or patient diagnosed with a condition / disease (e.g., hidradenitis suppurativa) to enable them to maintain their health in a state in which symptoms associated with the disease are significantly reduced, and will generally be a period of time beginning 8 weeks after the initial loading dose (given over 0-4 weeks) and treatment dose (given between 4-8 weeks). In one embodiment, the anti-IL-36R antibody maintenance therapy can continue after 8 weeks, including at least one subcutaneous dose, wherein each dose is 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg, given every 2 (q2w) or 4 (q4w) weeks after the last subcutaneous maintenance dose (e.g., between 4-8 weeks). In a non-limiting exemplary embodiment, at least 1800 mg of total maintenance dose followed by a maintenance therapy including at least one 600 mg, 900 mg, 1200 mg, 1800 mg, 2400 mg, or 3000 mg subcutaneous dose given between week 8 and week 52, preferably every two weeks (q2w).

[0153] As used herein, the terms "biweekly dosing regimen," "biweekly dosing," "q2w," and "biweekly administration" refer to the schedule over which an anti-IL-36R antibody, or antigen-binding portion thereof, is administered to a subject, e.g., throughout the course of treatment, to achieve therapeutic objectives. A biweekly dosing regimen is not intended to encompass a weekly dosing regimen. Preferably, the substance is administered every 9 to 19 days, or 10 to 18 days, more preferably every 11 to 17 days, or 12 to 16 days, even more preferably every 13 to 15 days, and optimally every 14 days. In one embodiment, a biweekly dosing regimen is initiated in a subject during the eighth week of treatment. In another embodiment, a maintenance dose is administered according to a biweekly dosing regimen. In one embodiment, both a loading dose and a maintenance dose are administered according to a biweekly dosing regimen. In one embodiment, biweekly dosing includes a dosing regimen in which a dose of the anti-IL-36R antibody, or antigen-binding portion thereof, is continuously administered to a subject every other week for a given 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.

[0154] As used interchangeably herein, the terms "qwk," "qw," or "ew" refer to a weekly dosing regimen, wherein an anti-IL-36R antibody, or antigen-binding portion thereof, is administered to a subject once a week (or weekly) to achieve a therapeutic goal, e.g., to treat HS. As used herein, a "weekly dosing regimen" refers to a schedule over which a substance (e.g., an anti-IL-36R antibody) is administered to a subject, e.g., throughout the course of treatment, to achieve a therapeutic goal. Weekly dosing can be more frequent than once every two weeks, e.g., every 6 to 8 days, every 5 to 8 days, or every 7 days.

[0155] The term "intravenous infusion" refers to the introduction of a pharmaceutical agent into a vein of an animal or human patient over a period of time greater than about 15 minutes, usually between about 30 and 90 minutes.

[0156] The term "intravenous bolus" or "intravenous push" refers to administering a drug into a vein of an animal or human so that the body receives the drug in about 15 minutes or less, typically 5 minutes or less.

[0157] The method of claim 11, further comprising administering to the individual subcutaneously a maintenance dose of at least 1200 mg, the maintenance dose comprising at least one dose of 300 mg, 600 mg, 900 mg, or 1200 mg of the anti-IL-36R antibody.

[0158] The term "subcutaneous administration" refers to the introduction of a pharmaceutical agent under the skin of an animal or human patient, preferably into the pocket between the skin and subcutaneous tissue, by relatively slow, sustained delivery from a drug reservoir. Pinching or pulling the skin away from the subcutaneous tissue can create a pocket.

[0159] The term "subcutaneous infusion" refers to the introduction of a drug from a drug container into the skin of an animal or human patient, preferably into a pocket between the skin and underlying tissue, by relatively slow, continuous delivery, for a period of time, including (but not limited to) 30 minutes or less, or 90 minutes or less. As appropriate, the infusion can be carried out 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, such as 30 minutes, 90 minutes, or a period of time spanning the length of a treatment regimen.

[0160] The term "subcutaneous bolus injection" refers to the administration of a drug under the skin of an animal or human patient, where the bolus injection drug delivery is less than about 15 minutes; in another aspect, less than 5 minutes, and in yet another aspect, less than 60 seconds. In even yet another aspect, the administration is into a pocket between the skin and underlying tissue, where the pocket can be created by pinching or pulling the skin away from the underlying tissue.

[0161] In view of the teachings herein, the dosing regimen described herein can be adjusted (e.g., in individual patients) to provide the optimal desired response, e.g., to maintain hidradenitis suppurativa remission.

[0162] It should be noted that dosage values can vary with the type and severity of the hidradenitis suppurativa. It should further be understood that the specific dosage regimen for any particular patient will depend upon a variety of factors, including the patient's general health status, age, sex, body weight, kind of concurrent treatment, if any, frequency of treatment, and the nature of the symptoms, and the judgment of the treating physician, and that dosage amounts set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed application.

[0163] "Pharmaceutical formulation" or "formulation" refers to the process in which an active drug or pharmaceutical agent is combined with chemical substances to produce a final pharmaceutical product or drug product, and to the process product, the final formulation thus referring to a pharmaceutical product such as a liquid, powder, or composition. Thus, in one embodiment, the pharmaceutical formulation is a pharmaceutical composition.

[0164] In this context, a "pharmaceutical composition" refers to a liquid or powder formulation that is in a form that allows the biological activity of the active ingredient to be clearly effective and that does not contain additional components that are significantly toxic to the individual to whom the composition will be administered. Such compositions are sterile. A "powder" refers to a freeze-dried or lyophilized or spray-dried pharmaceutical composition for parenteral use. The powder is typically reconstituted or dissolved in water. Lyophilization is a low-temperature dehydration process that involves freezing the product, reducing the pressure, and then removing the ice by sublimation. Freeze-drying results in a high-quality product because of the low temperatures used in the process. For a well-developed lyophilized formulation, the shape and appearance of the product remain unchanged over time and the quality of the reconstituted product is excellent. Spray-drying is another method that results in a dry powder from a liquid or slurry by rapid drying with hot gas and aims to achieve a constant particle size distribution.

[0165] As used herein, "buffer" refers to a buffered solution that resists changes in pH through the action of acid-base conjugate components. "pH" refers herein to the acidity or basicity 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 consists of calibrating the instrument, placing the electrode in a well-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.

[0166] As used herein, the term "tonicity adjusting agent" or "tonicity agent" or "tonic agent" refers to a substance that provides an osmotic pressure equivalent to that of serum in the body, including salts (e.g., sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g., sucrose, trehalose, sorbitol, magnesium sulfate (MgS04), glycerol, mannitol, or dextrose). Additionally, sugars present in the solution act as cryoprotectants for proteins, which allow the drug substance to be frozen without damage. This allows the drug substance to be shipped in frozen form and stored for long periods of time before the drug product is infused. Exemplary tonicity adjusting agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and / or sucrose, trehalose, sorbitol, magnesium sulfate (MgS04), glycerol, mannitol, or dextrose (sugars).

[0167] As used herein, the term "stabilizing agent" or "stabilizing agent" refers to a substance that aids in the stability of the active ingredient in a pharmaceutical formulation. Exemplary stabilizing agents of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or a pharmaceutically acceptable salt thereof.

[0168] As used herein, the term "surfactant" refers to a substance that tends to lower the surface tension of a liquid in which it is dissolved. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0169] In one embodiment related to any of the above aspects, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is present in a stable pharmaceutical formulation (as described in application 16 / 809,606, filed March 5, 2020, in the application, the entirety of which is hereby incorporated by reference herein in its entirety) to administer to the mammal or patient according to any of the aspects of the present invention.

[0170] In one embodiment, the method of treatment according to any of the aspects described herein, comprises administering to the mammal or patient a therapeutic amount of a stable pharmaceutical formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharmaceutically acceptable tonicity agent (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizer (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and an amount of a pharmaceutically acceptable surfactant (e.g., polysorbate 20) in an amount of about 0 g / L to about 1.5 g / L, wherein the patient's hidradenitis suppurativa (HS) is treated, prevented, or ameliorated, or the patient's skin disorder associated with HS is treated, or the patient's skin inflammation associated with HS is reduced or alleviated, or neutrophil infiltration in affected skin tissue of a subject with HS is prevented and / or reduced, or microbial colonization of the skin of a subject with HS is reduced, or susceptibility to skin infection of a subject with HS is reduced. Complete resolution of the patient's HS symptoms is achieved, or achieved. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the aqueous pharmaceutical formulation has a pH of about 5 to about 7. In a related embodiment, the pharmaceutical formulation is for intravenous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration comprises the anti-IL-36R antibody in an amount of about 60 mg / mL, wherein one vial contains 450 mg. In a related embodiment, the pharmaceutical formulation for subcutaneous administration comprises the anti-IL-36R antibody in an amount of about 150 mg / mL, wherein one pre-filled syringe contains 300 mg of the antibody for subcutaneous injection. Treatment of hidradenitis suppurativa

[0171] For purposes of treatment, the term "individual" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows and the like. Preferably, the mammal is a human.

[0172] Hidradenitis suppurativa (HS) is an inflammatory disease characterized by recurrent, painful abscesses and fistulae. More specifically, HS is a cutaneous disorder of apocrine glands (sweat glands found on certain parts of the body) and hair follicles, in which swollen, painful, inflamed lesions or lumps appear in the groin and sometimes in the axilla and submammary region. Hidradenitis suppurativa occurs when the apocrine gland outlet is blocked by sweat or fails to drain properly due to incomplete gland development. Trapped secretions in the gland force sweat and bacteria into the surrounding tissue, causing subcutaneous induration, inflammation, and infection. Hidradenitis suppurativa is limited to areas of the body that contain apocrine glands. These areas are the axillary, nipple areola, inguinal, perineal, perianal, and periumbilical regions.

[0173] HS individuals are objectively one of the lowest quality of life measures among any skin disease. Lesions typically occur in the axillary, inguinal, submammary, and / or anogenital regions of the body. HS lesions can progress to form sinus tracts and expanding abscesses. Sequelae include significant pain, scarring, and psychological distress. IL36 ligands have been shown to be upregulated in lesional skin and in circulation of HS individuals (Di Caprio et al., 2017; Hessam et al., 2018; Thomi et al., 2017).

[0174] Despite the absence of animal model data for HS, expression and function of this pathway in various disease-relevant cell types links it to 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). Mice lacking the IL36R receptor have significantly reduced skin inflammation and keratinocyte proliferation compared to wild-type controls.

[0175] IL36R is a novel member of the IL1R family that forms heterodimeric complexes with IL1R accessory protein (IL1RAcp) and IL1Rrp2, which is associated with epithelial-mediated inflammation and barrier dysfunction. The heterodimeric IL36R system with stimulatory (IL36a, IL36b, IL36y) and inhibitory ligands (IL36Ra and IL38) shares multiple structural and functional similarities with other members of the IL1 / ILR family, such as IL1, IL18, and IL33. All IL1 family members (IL1a, IL1b, IL18, IL36a, IL36b, IL36y, and IL38) signal through unique cognate receptor proteins that, upon ligand binding, recruit the common IL1RacP subunit in receptor-positive cell types and activate NFkB and MAP kinase pathways (Dinarello, 2011; Towne et al., 2004; Towne et al., 2011

[0176] Accordingly, the present application includes methods for treating an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof. As used herein, "an individual in need thereof expressing" means a human or non-human animal expressing one or more symptoms of hidradenitis suppurativa (HS), such as neutrophil infiltration in affected skin tissue, pustules, etc., and / or has been diagnosed with a HS condition.

[0177] In one embodiment, an individual having hidradenitis suppurativa can also have a skin infection selected from the group consisting of impetigo, cellulitis, infected dermatitis, nummular eczema, folliculitis, infected blisters, mycosis, tinea versicolor, Staphylococcus aureus infection, and Streptococcus infection. Microorganisms causing the infection include, but are not limited to, Staphylococcus aureus, Streptococcus, Pseudomonas aeruginosa, Bacteroides, Herpes simplex virus, Coxsackie virus, Molluscipoxvirus, Vaccinia virus, Candida albicans, Microsporum, Trichophyton, Penicillium, Cladosporium, Alternaria, and Aspergillus.

[0178] The present application provides methods of reducing microbial colonization of the skin of an individual having hidradenitis suppurativa, comprising administering to the individual a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof. In certain embodiments, the present application provides methods of reducing colonization of Staphylococcus aureus on the skin of an individual having a neutrophilic dermatosis. 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 following administration of the anti-IL-36R antibody.

[0179] Microbial colonization can be measured using tests and procedures known in the art, for example by 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, for example microbial toxins such as Staphylococcal Toxic Shock Syndrome Toxin-1. Methods for detecting and / or quantifying such biomarkers are known in the art.

[0180] As used herein, the terms "treat," "treating" or the like mean to alleviate symptoms, eliminate the causation of symptoms, or prevent or slow the appearance of symptoms of the indicated disorder or condition, on a temporary or permanent basis. These terms are intended to encompass treatment of a disease or disorder as well as prophylactic or preventative measures, including, but not limited to, alleviating or abating one or more symptoms, remission, slowing or arresting disease or disorder progression. Thus, for example, the term treatment includes the administration of an agent prior to or following the onset of symptoms of a disease or disorder, thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes the administration of an agent following the clinical expression of a disease to combat symptoms of the disease. Furthermore, administration of an agent following the onset and after clinical symptoms have developed, where the treatment affects a clinical parameter of the disease or disorder, such as the extent of tissue damage, whether or not the treatment results in improvement of the disease, includes "treatment" or "therapy" as used herein. In addition, results are considered effective treatment of the underlying disorder if the composition of the application, alone or in combination with another therapeutic agent, alleviates or improves at least one symptom of the disorder being treated, regardless of whether all symptoms of the disorder are alleviated.

[0181] 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 aspect, a therapeutically effective amount refers to a target serum concentration that is shown to be effective, e.g., to slow progression of the disease. Efficacy can be measured by methods known to one of skill in the art, for example by the measurements and methods described below, wherein the proportion of individuals having a response to administration against IL36R is statistically significantly higher than individuals using a placebo for one or more of the endpoints assessed.

[0182] The term "prophylactically effective amount" is used to refer to an amount effective, at dosages and for periods of time necessary to achieve the desired prophylactic result. Typically, a prophylactic dose is used in a subject prior to or at the onset of symptoms of HS, in order to prevent or inhibit the occurrence of an episode of HS. In one embodiment, a subcutaneous dose as contemplated herein is a prophylactic dose used in a patient with acute HS following an intravenous dose to prevent possible recurrence of HS in the patient. Therapeutic endpoints:

[0183] Embodiments of the present application provide a means for treating individuals suffering from moderate to severe hidradenitis suppurativa.

[0184] In other embodiments, the present application provides improved methods of treatment, including methods of improving disease reduction in individuals with hidradenitis suppurativa and improving the quality of life of individuals with hidradenitis suppurativa.

[0185] In other embodiments, the present application provides a method of treating certain subpopulations of individuals, including, for example, individuals for whom previous therapy has failed or who have had a suboptimal response to therapy, including, for example, individuals who have had an inadequate response to or are intolerant of or have a contraindication to oral antibiotics. In certain embodiments, the present application is used to treat HS in individuals who have had an inadequate response to or are intolerant of oral antibiotics for the treatment of their hidradenitis suppurativa, or individuals who have had an inadequate response to or are intolerant of or have a contraindication to TNF-a inhibitors. In certain embodiments, the present application is used to treat HS in individuals who have had an inadequate response to or are intolerant of TNF-a for the treatment of their hidradenitis suppurativa.

[0186] The methods and uses described herein provide a means of determining the efficacy of an anti-IL-36R antibody, or antigen-binding portion thereof, in the treatment of hidradenitis suppurativa, and the use of such anti-IL-36R antibodies for the treatment of hidradenitis suppurativa. Treatment of HS can be determined using any of the measures described herein or any measure known in the art, for example: (a) the percent change from baseline in dT count at week 12 (b) achievement of hidradenitis suppurativa clinical response (HiSCR) at week 16. (c) the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4) value at week 12 (d) the absolute change from baseline in Hidradenitis Suppurativa Area and Severity Index (HASI) score at week 12 (e) achievement of at least a 30% reduction from baseline in the Numeric Rating Scale (NRS30) of patient's overall assessment of pain from HS at week 12 (f) achievement of Physician's Global Assessment (PGA) score of 0 or 1 at week 12 (g) the complete resolution of dTs at week 12 (h) the occurrence of at least one flare (defined as at least a 25% increase in AN count from baseline up to week 12, with a minimum increase of 2. (i) the absolute change from baseline in Dermatology Life Quality Index (DLQI) score at week 12. (j) Absolute change from baseline in the Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at week 12.

[0187] In another embodiment related to the above embodiment or the first to seventh aspects, the administration produces one or more of the following efficacy assessment indicators: (a) Percent change in dT counts from baseline at Week 8 and / or Week 16; (b) absolute change from baseline in IHS4 value at week 8 and / or week 16; (c) Hidradenitis suppurativa area severity index (HASI) at week 16 absolute change in score from baseline; (d) achieving hidradenitis suppurativa clinical response (HiSCR50) at week 16; (e) percent change in abscess count from baseline at week 16; (f) Achieve at least a 50% reduction in dT counts relative to baseline at Week 16;\ (g) achieve at least a 50% reduction in abscess and dT (AdT) counts relative to baseline at Week 16; (h) achieve at least a 50% reduction in ANdT counts relative to baseline at Week 16; (i) achieve at least a 30% reduction in the patient's global assessment of HS pain on a numerical rating scale (NRS30) compared to baseline at Week 16; (j) Percent change from baseline in dT counts at each scheduled assessment; (k) Achieve at least 50% dT counts relative to baseline at each scheduled assessment reduce; (l) Complete elimination of dT occurs at each scheduled assessment; (m) time to complete elimination of the first occurrence of dT during the treatment period; (n) percent change from baseline in abscess count at each scheduled assessment; (o) Achieve at least a 50% reduction in abscess count relative to baseline at each scheduled assessment reduce; (p) complete resolution of the abscess at each scheduled assessment; (q) percent change from baseline in total AdT counts at each scheduled assessment; (r) Achieve at least 50% of AdT count relative to baseline at each scheduled assessment reduce; (s) Percent change from baseline in inflammatory nodule (N) count at each scheduled assessment; (t) achieve at least a 30% reduction from baseline in the Numerical Rating Scale (NRS30) for the patient's global assessment of HS pain at each scheduled assessment; (u) absolute change from baseline in the 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; (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) Hidradenitis suppurativa odor and discharge scale at each scheduled assessment (HODS) change from baseline; (aa) Change from baseline in NRS pruritus at each scheduled assessment; (bb) change from baseline in the Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment; (cc) Percent change from baseline in total ANdT counts at each scheduled assessment; or (dd) Achieve at least 50% ANdT count relative to baseline at each scheduled assessment reduce.

[0188] In another embodiment related to the above embodiments or aspects, the proportion of subjects who respond to administration is statistically significantly greater than that of subjects who receive placebo for one or more of the assessment criteria (a)-(j) and / or (a)-(dd).

[0189] In another embodiment related to the above embodiment, the present invention provides a method for reducing the number of inflammatory lesions (AN count) or achieving hidradenitis suppurativa clinical responsiveness (HiSCR) in a subject with HS, the method comprising systemically administering an isolated human anti-IL36R antibody, or an antigen-binding portion thereof, to the subject such that the AN count is reduced. Clinical responsiveness according to the HiSCR scoring system is defined as a decrease in total AN count of at least 50% relative to baseline and no increase in abscess or draining fistula count.

[0190] In another embodiment related to the above embodiment, the subject does not have an increase in abscess count and / or an increase in draining fistula or tract (dT) count following administration of the anti-IL36R antibody, or antigen-binding portion thereof.

[0191] In another embodiment related to the above embodiments, the present application provides a method of reducing the severity of HS according to the IHS4 score, which is an absolute change from baseline in assessing the severity of HS according to the International Hidradenitis Suppurativa Severity Score System (IHS4). Determining the IHS4 requires counting nodules, abscesses, and draining fistula / sinuses. The absolute change from baseline or "IHS4" score assesses the severity of HS and the resulting IHS4 score is achieved by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tubes (multiplied by 4). A total score of 3 or less indicates mild, 4-10 indicates moderate, and 11 or higher indicates severe disease.

[0192] In another embodiment related to the above embodiments, the present application provides a method for improving (or reducing) the severity of symptoms of HS as measured by the severity of HS symptoms from a higher score (e.g., HASI score of 3 or greater in one or more areas) to a no or low impact score (e.g., HS-PGA score of 0-2) in a subject having hidradenitis suppurativa according to the Hidradenitis Suppurativa Area and Severity Index (HASI) score, comprising administering to the subject an IL-36R inhibitor, e.g., a human IL-36R antibody or antigen-binding portion thereof, such that the HASI score improves from a high score to a no or low impact score. The HASI score model is modeled after the Psoriasis Area and Severity Index (PASI). Four cardinal signs of HS-related inflammation (erythema, induration, open ulcer, and draining tube) are included. Each variable of HASI for each predetermined body region is scored on a Likert scale (0-3). For BSA assessment, the number of palms involved for each body region (head, right axilla, left axilla, anterior chest, back, anterior bathing trunk, posterior bathing trunk, other) is assessed (one palm indicates 1% of patient BSA). This is converted to a percentage of the region. Area scores are assigned to each region using the PASI method (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 4 clinical variable scores is multiplied by the area score for each involved region. This value is then multiplied by the proportion of BSA of that region to give the local HASI score. Local HASI scores are added together to give the cumulative total HASI score (range 0-72). "HASI" combines the assessment of lesion severity and affected region into a single score ranging from 0 (no disease) to 72 (severe disease).

[0193] In another embodiment related to the above embodiments, the present application provides a method of improving (i.e., reducing) the Physician's Global Assessment (HS-PGA) score of hidradenitis suppurativa. The present application also provides a method of reducing the HS PGA score of an individual having hidradenitis suppurativa by at least about 2 grades, comprising administering an IL36R inhibitor, e.g., a human IL36R antibody or antigen-binding fragment thereof. The HS-PGA document is a physician's assessment of a patient's HS at a specified time point. It scores the patient's disease severity as clear, minimal, mild, moderate to severe, or very severe based on 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, where 0 (clear: no abscesses, draining tubes, inflammatory nodules, or non-inflammatory nodules), 1 (minimal: no abscesses, draining tubes, or inflammatory nodules and presence of non-inflammatory nodules), 2 (mild: no abscesses or draining tubes and 1-4 inflammatory nodules or 1 abscess or draining tube and no inflammatory nodules), 3 (moderate: no abscesses or draining tubes and >5 inflammatory nodules or 1 abscess or draining tube and >1 inflammatory nodule or 2-5 abscesses or draining tubes and <10 inflammatory nodules), 4 (severe: 2-5 abscesses or draining tubes and >10 inflammatory nodules), 5 (very severe: >5 abscesses or draining tubes).

[0194] In another embodiment related to the above embodiments, the present application provides a method of reducing the HS-PGA score of an individual having hidradenitis suppurativa from a higher score (e.g., 3 or higher) to a no or minimal impact score (e.g., 0 to 2), comprising administering to the individual a human IL-36R antibody, such that the HS-PGA score is reduced from the higher score to the no or minimal impact score.

[0195] In another embodiment related to the above embodiments, the present application provides a method of reducing the HS-PGA score of an individual having hidradenitis suppurativa by at least about 2 grades, comprising administering to the individual a human IL-36R antibody, such that the HS-PGA score is reduced by at least about 2 grades.

[0196] In another embodiment related to the above embodiments, the Numerical Rating Scale (NRS30) of the patient's global assessment of Hidradenitis Suppurativa (HS) pain can also be used as an index to measure the effectiveness of an anti-IL36R antibody, or antigen-binding portion thereof, in a patient or population of patients having Hidradenitis Suppurativa, wherein a mean statistically significant (compared to placebo) improvement in the NRS30 pain score of at least 30% within the treated population of individuals is indicative of the IL-36R antibody being effective in treating Hidradenitis Suppurativa. The HS pain NRS is an assessment indicator used in clinical trials to assess the severity of HS-related pain in individuals with HS. Responses are given on an 11-point scale ranging from 0 (no HS pain) to 10 (HS pain is unimaginable). In related embodiments, the present application provides a method for determining whether a human IL-36R antibody is effective in treating Hidradenitis Suppurativa based on an improvement in the NRS30 pain score.

[0197] In another embodiment related to the above embodiments, the present application provides a method of improving the Dermatology Life Quality Index (DLQI) score of an individual having Hidradenitis Suppurativa from a high score (i.e., impaired quality of life) to a low score (i.e., quality of life is not or less affected), comprising administering to the individual a human IL-36R antibody, such that the DLQI score is reduced from a high score to a low score. The DLQI is a quality of life questionnaire given to patients containing ten questions that cover six areas, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Joint Ann Mtg of the British Association of Dermatologists and the Canadian Dermatology Association, Oxford, 6-10 Jul 1993. Clin Exp Dermatol 1994; 19: 210-216). The DLQI has a one-week recall period. Response categories include "not relevant" (score of 0), "not at all" (score of 0), "a little" (score of 1), "a lot" (score of 2), and "a great deal" (score of 3). Question 7 is a "yes" / "no" question, with a "yes" score of 3. The total DLQI score is calculated by summing the scores for each question resulting in a range of 0 to 30. The higher the score, the more impaired the quality of life.

[0198] In another embodiment related to the above embodiments, the present application provides a method of improving the hidradenitis suppurativa quality of life (HiS-QoL) score of an individual having hidradenitis suppurativa from a high score (i.e., quality of life is highly affected) to a low score (i.e., low impact on quality of life), comprising administering to the individual a human IL-36R antibody such that the HiS-QoL score decreases from the high score to the low score. The HiS-QoL questionnaire is a 17-item instrument administered to patients to measure HS-specific quality of life in clinical trials. The 17 HiS-QoL includes four symptom items, eight activity accommodation items, and five psychosocial items. The items are summed to produce a total score ranging from 0 to 68, where a higher score indicates a more severe impact on quality of life.

[0199] In another embodiment related to the above embodiments, the present application provides a method of improving the symptoms of HS or reducing the severity of pruritus associated with HS as scored according to the Numerical Rating Scale for Pruritus (NRS Pruritus), comprising administering to the individual a human IL-36R antibody such that the score decreases from the high baseline score to a low score. The HS Pruritus NRS is an assessment indicator used to assess the severity of HS-related pruritus in individuals with HS in clinical trials. Patient global assessment of HS pruritus assesses the worst HS pruritus. The rating ranges from 0 (no itch) to 10 (worst imaginable itch). It is a unidimensional measure of pruritus intensity and can be administered daily with minimal burden to the trial participant. The recall period is 24 h and the response is given through an 11-point scale ranging from 0 (“no itch”) to 10 (“worst imaginable itch”). The trial participant is asked to rate their itch intensity using this scale.

[0200] In another embodiment related to the above embodiments, the present application provides a method of improving the symptoms of HS or reducing the incidence of drainage and odor caused by clinical symptoms of HS according to the Hidradenitis Suppurativa Odor and Drainage Scale (HODS), comprising administering to the individual a human IL-36R antibody such that the score decreases from the high baseline score to a low score. The HODS is an 8-item scale developed to assess HS-related drainage and odor in individuals. It encompasses two domains: drainage (5 items) and odor (3 items). Response options range from 1 to 5. A higher score depicts a worse outcome of the concept assessed.

[0201] In another embodiment related to the above embodiments, the present application provides a method of reducing and / or improving anxiety and / or depression in a subject with HS according to the Hospital Anxiety and Depression Scale (HADS), comprising administering to the subject a human IL-36R antibody such that the score is reduced from the high baseline score to a low score. The HADS is an instrument for screening anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 for each of anxiety and depressive symptoms; the possible score range for the subscales is 0 to 21.

[0202] In another embodiment related to the above, the present application provides a method of improving work productivity and / or total activity in a patient with HS according to the Work Productivity and Activity Impairment Questionnaire: HS (WPAI-HS), comprising administering to the subject a human IL-36R antibody such that the score is reduced from the high baseline score (high impact) to a low score (low impact). The WPAI-HS is a 6-item instrument to assess the impact of hidradenitis suppurativa on the ability to work and perform normal daily activities.

[0203] In another embodiment related to the above embodiments, the present application provides a method of reducing the impact on a patient's quality of life and / or improving a patient's overall quality of life as assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L), comprising administering to the subject a human IL-36R antibody, wherein the improvement changes 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 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, assessing the pointer marking "best possible health" and "worst possible health."

[0204] In another embodiment related to the above embodiments, the proportion of subjects who respond to the administration of an anti-IL36R antibody is statistically significantly higher compared to subjects using a placebo for one or more of the assessment indicators.

[0205] In one aspect, the present application relates to a method of treating and / or preventing a relapse of symptoms of HS in a patient treated with one or more intravenous doses of an anti-IL-36R antibody according to any of the aspects or above embodiments, the method comprising administering to the patient a therapeutically effective amount of an anti-IL-36R antibody in one or more subcutaneous doses.

[0206] In one aspect, the present application relates to a method of achieving a 50% reduction in total AN count from baseline in a patient treated with one or more doses of an anti-IL-36R antibody according to any of the aspects of the embodiments above, wherein there is no increase in abscess or draining fistula count, comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more intravenous and / or subcutaneous doses.

[0207] In one aspect, the present application 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 non-parenteral doses of an anti-IL-36R antibody according to any of the aspects or embodiments above, wherein the HS symptoms include inflammatory lesions, abscesses, draining fistula / sinuses or tunnels (dTs), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection, and / or HS-associated pain.

[0208] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement by week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by percent change in total AN count from baseline.

[0209] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement in the appearance of HS flares by week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment (appearance of a flare is defined as an increase of at least 25% in AN count from baseline total AN count, with a minimum increase of 2).

[0210] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement by week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by percent change in total dT count from baseline.

[0211] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit complete elimination of dTs at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0212] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals achieve a clinical response measured by a Hidradenitis Suppurativa Clinical Response Score, HiSCR, defined by at least a 50% reduction in total AN count from baseline without an increase in abscess or draining fistula count at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0213] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement measured by an absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4) at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0214] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a significant clinical improvement measured by an absolute change from baseline in the Hidradenitis Suppurativa Area and Severity Index (HASI) at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0215] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a 30% reduction from baseline in the Numerical Rating Scale (NRS30) of the patient’s global assessment of HS pain at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0216] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a Physician's Global Assessment (PGA) score of 0 or 1 at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

[0217] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a clinical improvement at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by the absolute change from baseline in the Dermatology Life Quality Index (DLQI) score.

[0218] In one embodiment related to any of the above aspects or related embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the individuals exhibit a clinical improvement at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by the absolute change from baseline in the Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score.

[0219] In a related embodiment, the proportion of individuals with a response to the administration is statistically significantly higher than individuals using a placebo for any of the listed assessment metrics. Pharmaceutical dosage and administration

[0220] The anti-IL-36R antibodies of the present application are typically administered to a patient in the form of a pharmaceutical composition, wherein the antagonist is combined with a pharmaceutically acceptable carrier or excipient, see, e.g., Remington's Pharmaceutical Sciences and US. 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, syrups, 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, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; 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, N.Y.). Suitable routes of administration include intravenous injection (including intraarterial injection) and subcutaneous injection.

[0221] In one embodiment, the present application provides a method for treating an individual having hidradenitis suppurativa (HS), the method comprising administering to the individual an isolated human anti-IL-36R antibody, or antigen-binding portion thereof, according to a plurality of variable dose regimens, such that HS is treated, wherein the plurality of variable dose regimens 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, wherein the total loading dose of the anti-IL-36R antibody is at least 1200 mg, 1350 mg, 1600 mg, 1800 mg, 2400 mg, 2700 mg, 3600 mg, 4800 mg, 5400 mg, or 7200 mg.

[0222] In another embodiment, the anti-IL-36R antibody is administered in one intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in at least one intravenous dose of 450 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 600 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 900 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 1200 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 1800 mg.

[0223] In another embodiment, 1, 2, 3, or 4 intravenous doses are administered. In another embodiment related to any of the above aspects, 2, 3, or 4 intravenous doses are administered at 1, 2, 4, 6, 8, 10, or 12 week intervals.

[0224] In another embodiment, 1, 2, 3, or 4 intravenous doses and at least 1, 2, 3, 4, or 5 subcutaneous doses are administered to the individual at 1, 2, 4, 6, 8, 10, or 12, 16 week intervals after the last intravenous dose.

[0225] In one embodiment, the present application provides a method for treating an individual having hidradenitis suppurativa (HS), the method comprising administering to the individual an isolated human anti-IL-36R antibody, or antigen-binding portion thereof, according to a plurality of variable dose regimens, such that HS is treated, wherein the plurality of variable dose regimens 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, 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 comprising one or more intravenous doses of 450 mg, 900 mg, 1200 mg, or 1800 mg of the anti-IL-36R antibody. In a related embodiment, the anti-IL-36R antibody is administered at 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 at 1, 2, 3 to 4 week intervals.

[0226] In one embodiment related to 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 1200 mg intravenous doses are delivered at week 0, week 1, and week 2, for a total loading dose of 3600 mg.

[0227] In one embodiment related to 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 every two weeks at week 4, week 6, week 8, week 10, and week 12.

[0228] In one embodiment related to 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 non-limiting exemplary embodiments, four intravenous doses of 450 mg are delivered at weeks 0, 1, and 2, 3 for a total loading dose of 1800 mg; four intravenous doses of 900 mg are delivered at weeks 0, 1, and 2, 3 for a total loading dose of 3600 mg; or four intravenous doses of 1800 mg are delivered at weeks 0, 1, and 2, 3 for a total loading dose of 7200 mg.

[0229] In one embodiment related to 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 at weeks 4, 5, 6, and 7. In non-limiting exemplary embodiments, four subcutaneous doses of 300 mg are delivered once weekly at weeks 4, 5, 6, and 7 for a total maintenance dose of 1200 mg; four subcutaneous doses of 600 mg are delivered once weekly at weeks 4, 5, 6, and 7 for a total maintenance dose of 2400 mg; or four subcutaneous doses of 1200 mg are delivered once weekly at weeks 4, 5, 6, and 7 for a total maintenance dose of 3600 mg. In a related embodiment, at least one subcutaneous dose is administered after the final intravenous dose.

[0230] In one embodiment related to the above maintenance doses, in non-limiting exemplary regimens, the anti-IL-36R antibody is administered subcutaneously at a dose of 600 mg or 1200 mg biweekly after the last subcutaneous dose comprising the maintenance dose.

[0231] Representative examples of dosages and dosing regimens according to the present application are disclosed in Tables 12 and Tables 22 and 23. Antibodies of the Invention

[0232] Anti-IL36R antibodies of the present application are disclosed in U.S. Patent No. 9,023,995 or WO2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0233] As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains (two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region (abbreviated herein as HC or CH). In a typical antibody, each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region (abbreviated herein as LC or CL). The variable regions of each heavy and light chain pair to form the antibody binding site. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors. The term "antibody" also includes any antigen binding portion of an antibody that binds an IL-36R, including but not limited to F(ab')2, Fab', Fab', Fv, and Fd fragments.H ) and a heavy chain constant region. The heavy chain constant region contains three domains, C H 1, C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region. The light chain constant region includes one domain (C L 1). The V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the application, the FRs of an anti-IL-36R antibody (or antigen-binding portion thereof) can be identical to the human germline sequences or can be naturally or artificially modified. Amino acid consensus sequences can be determined based on a side-by-side analysis of two or more CDRs.

[0234] As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and like terms include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. An antigen-binding fragment of an antibody can be derived from, e.g., an intact antibody molecule using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and, where appropriate, constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, e.g., to configure one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0235] 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 the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR), such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. 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 are also encompassed within the expression "antigen binding fragment" as used herein.

[0236] Antigen binding fragments of antibodies will typically comprise at least one variable domain. The variable domain can be of any size or amino acid composition and is generally understood to include at least one CDR which is either adjacent to or in frame with one or more framework sequences. In some embodiments, the antibody comprises a V L In some embodiments, the antibody comprises a V H In some embodiments, the antibody comprises a V H In some embodiments, the antibody comprises a V L The V H The V H The V H The V L The V L The V L In some embodiments, the antibody comprises a V H In some embodiments, the antibody comprises a V L

[0237] Antibodies used in the methods of the application can 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. The human antibodies of the application can nevertheless 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 and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0238] ​Antibodies used in the methods of the application can be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed from a recombinant H and V L regions of the recombinant antibodies have amino acid sequences which derive from, and relate back to, the human germline immunoglobulin sequences, but which may, nonetheless, not naturally exist within the human antibody germline repertoire in vivo. H and V L sequences, but which are sequences which can not naturally exist within the human antibody germline repertoire in vivo.

[0239] According to certain embodiments, the antibodies used in the methods of the application specifically bind IL-36R. The term "specifically binds" or its like terms means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" IL-36R, as used in the context of the present application, includes an antibody that binds IL-36R or a portion thereof, wherein K D 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 in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-36R can have cross-reactivity with other antigens, such as IL-36R molecules from other (non-human) species.

[0240] In certain illustrative embodiments related to any aspect of the application, the anti-IL-36R antibody or antigen-binding fragment thereof that can be used in the context of the methods of the application includes: a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53 or 141; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72.

[0241] According to certain embodiments, the anti-IL-36R antibody or antigen-binding fragment thereof comprises: i. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 102; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or ii. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 103; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iii. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 104; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or iv. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 105; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or v. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 106; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or vi. a) a light chain variable region (L-CDR1) comprising the amino acid sequence of SEQ ID NO: 26; a light chain variable region (L-CDR2) comprising the amino acid sequence of SEQ ID NO: 140; a light chain variable region (L-CDR3) comprising the amino acid sequence of SEQ ID NO: 44; and b) a heavy chain variable region (H-CDR1) comprising the amino acid sequence of SEQ ID NO: 53; a heavy chain variable region (H-CDR2) comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111; a heavy chain variable region (H-CDR3) comprising the amino acid sequence of SEQ ID NO: 72; or vii. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); a light chain variable region comprising the amino acid sequence of SEQ ID NO: 104 (L-CDR2); a light chain variable region comprising 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); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0242] According to 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.

[0243] According to 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.

[0244] In one aspect, described and disclosed herein are anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, and compositions and articles of manufacture comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies of the present disclosure. Also described are binding agents comprising antigen-binding fragments of anti-IL-36 antibodies, particularly humanized anti-IL-36R antibodies.

[0245] In one aspect, the anti-IL-36R antibodies described and disclosed herein are pisotimomab. Mode of action

[0246] The anti-IL-36R antibodies of the present invention are humanized antagonistic monoclonal IgGl antibodies that block human IL36R signaling. Binding of the anti-IL-36R antibodies of the present invention to IL36R is expected to prevent subsequent activation of IL36R by cognate ligands (IL36a, b and g), and downstream activation of proinflammatory and profibrotic pathways, with the aim of reducing epithelial / fibroblast / immune cell-mediated inflammation and interrupting the inflammatory response that drives pathogenic cytokine production.

[0247] IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been reported that agonistic IL-36 ligands (a, b or g) initiate a signaling cascade by engaging the IL-36 receptor, which then forms 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. Articles of manufacture

[0248] In another aspect, articles of manufacture containing materials useful for the treatment of the conditions described above are provided. The articles of manufacture comprise a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. The containers hold a composition which is effective for treating the condition and can have a sterile access port (for example, by a stopper pierceable by a hypodermic injection needle). For example, the container can be an intravenous solution bag or a vial of the composition containing a unit dose of the humanized anti-IL-36R antibody. When the composition is a

[0249] The term "pharmaceutical package insert" is used to refer to the instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosing, contraindications and / or warnings associated with the use of such therapeutic products.

[0250] The present invention is further described in the following examples, which are not intended to limit the scope of the present invention. Examples

[0251] The following examples are intended to further illustrate certain preferred embodiments of the present invention and are not intended to limit the scope of the present invention. One skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Example 1: Phase IIa clinical trial: Treatment of individuals with hidradenitis suppurativa

[0252] Objectives:

[0253] Currently, adalimumab (TNFi) is the only approved biologic for HS, with a response rate of 42-59%, compared to 26-28% for placebo, with a time course of weekly subcutaneous administration. In terms of evidence of efficacy and safety, even the available treatment options for controlling HS, completely eliminating symptoms, and preventing recurrence of HS have their limitations. In addition, HS treatment has long-term safety issues compared to other inflammatory diseases such as psoriasis, in which the administration regimen of biologics is generally more intensive. In view of the above, there is an urgent need for more effective and safer molecules and better administration regimens for HS patients.

[0254] IL-36a, b and g mRNA expression is upregulated in lesional skin of HS individuals and 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 ligands was also confirmed by in situ hybridization staining of HS lesions. IL-36 is considered a central upstream mediator of the inflammatory loop, which further activates keratinocytes, increases secretion of chemotactic cytokines, and thus causes infiltration of immune cells into the skin. Infiltrating dendritic cells (DCs) and monocytes can be activated by IL-36 (internal and published data) to enhance the antigen-presenting cell function of DCs and also cause secretion of chemotactic cytokines and cytokines, which can recruit more immune cells, including neutrophils. IL-36 is a potent activator of neutrophil infiltration, and in the case of HS, neutrophils were shown to undergo netosis, causing secretion of AMPs 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 driving TH17 and TH1 responses and animal models of atopic dermatitis (AtD), it was hypothesized that IL-36 can be a key driver of TH17 responses in the skin of HS patients. Given this, pesanilumab can be beneficial for the treatment of HS.

[0255] In this example, anti-IL36R antibodies of the application are used to treat patients with hidradenitis suppurativa. The aim of this study is to find out whether a drug called pesanilumab helps people with moderate to severe hidradenitis suppurativa.

[0256] The primary objective of this trial is to assess the effect of pexelizumab compared to placebo on the mean percent change from baseline in total abscess and inflammatory nodule (AN) count at Week 12 in individuals with moderate to severe HS. Secondary objectives are the assessment of the efficacy of pexelizumab compared to placebo on secondary efficacy measures. The comparisons of interest for each efficacy objective are the comparisons of all treated individuals, but excluding the effect of rescue therapy. Other objectives of this trial are to assess the efficacy of pexelizumab in individuals with HS, the PK, additional measures of anti-drug antibodies (ADA), and exploratory of specific biomarkers.

[0257] HS is characterized by recurrent, painful abscesses and fistulas. Individuals with HS are objectively among the patients with the lowest quality of life measures of any skin disease. Lesions typically occur in the axillary, inguinal, inframammary, or anogenital regions of the body. HS lesions can progress to form sinus tracts and dilated abscesses. Sequelae include significant pain, scarring, and psychological distress. The mean age of onset is in the early twenties (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). Global prevalence of HS has been reported to be between 0.0003% and 4.1%. Underdiagnosis or misdiagnosis is common. Overall, HS prevalence varies significantly based on study methodology; however, the disease appears 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).

[0258] From a patient perspective, some of the most severe HS symptoms are pain, draining and bursting open, itching, skin tautness (scarring), odor, fatigue, and flu-like symptoms. It has been reported that individuals are not satisfied with the degree of control provided by current available treatment regimens; unmet needs from a patient perspective include the need for new medical treatments with a good efficacy and tolerability profile. In qualitative evidence, the most important treatment goals from a patient perspective were pain, draining (including bursting open), and fatigue.

[0259] In Phase Ila trial 1368.52, participants were divided into 2 groups: placebo or participants using pesonalizumab. Participants were infused with pesonalizumab or placebo into a vein weekly for the first 3 weeks. Then, they were injected subcutaneously with pesonalizumab or placebo every 2 weeks.

[0260] The primary objective of the Phase Ila trial was to assess the effect of pesonalizumab compared to placebo on the mean percent change from baseline in total abscess and inflammatory nodule (AN) count at Week 12 in individuals with moderate to severe HS. Secondary objectives were the assessment of the efficacy of pesonalizumab compared to placebo on secondary efficacy measures. The comparisons of interest for each efficacy objective were the comparisons of all treated individuals, but excluding the effect of rescue therapy.

[0261] Other objectives of this trial were to assess the efficacy of pesonalizumab in individuals with HS, PK, additional measures of anti-drug antibodies (ADA), and exploration of specific biomarkers.

[0262] Overall design:

[0263] A parallel-group, randomized, double-blind, and placebo-controlled trial was considered the most appropriate to demonstrate PoC. A placebo-controlled arm was needed to compare the efficacy and safety of pesonalizumab in individuals with moderate to severe HS who were biologic treatment naive or who had failed previous TNFi treatment. And a 2: 1 randomization scheme could help reduce the number of individuals assigned to the placebo arm. In addition, individuals were invited to roll over to an OLE trial in which they took the active drug if eligible.

[0264] A treatment duration of 12 weeks with pesonalizumab was chosen to assess sustained efficacy in individuals with HS.

[0265] Three intravenous loading doses followed by maintenance subcutaneous dosing every two weeks were chosen to optimize the exposure of pesonalizumab to assess its efficacy in HS. The intravenous loading doses were chosen to maximize the treatment response, the duration of response, and to reach steady state earlier. The loading doses were also considered to allow for an earlier onset of response. The maintenance doses were then given subcutaneously in order to maintain the response.

[0266] Phase IIa trial 1368.52 was an international, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of pesonapront in individuals with moderate to severe HS. A total of 52 individuals (pesonapront: 36 individuals; placebo: 16 individuals). After screening, individuals who met all eligibility criteria were randomized in a 2: 1 ratio to the active or placebo group. Randomization was stratified for the TNFi naive population compared to the TNFi failure population. It was planned that approximately 33 individuals from the TNFi naive population and 12 individuals from the TNFi failure population were randomized, respectively. Primary failure of TNF therapy was defined as lack of efficacy after at least 3 months of treatment with an agent blocking TNF-alpha, and secondary failure was defined as loss of clinical efficacy in patients after initial response to an agent blocking TNF-alpha.

[0267] Once randomized, individuals started a 12-week treatment period (see Figure 3A ), with a loading dose of pesonapront 3600 mg intravenously (1200 mg intravenously q1w) or matching placebo, followed by maintenance subcutaneous dosing of 1200 mg pesonapront q2w or matching placebo.

[0268] For the ongoing open-label, long-term extension trial (1368.67), an interim analysis was conducted in HS individuals who had completed treatment in trial 1368.52. Individuals from the placebo arm of the 1368.52 trial were given an initial 1200 mg intravenous loading dose of pesonapront plus subcutaneous placebo, followed by 600 mg pesonapront subcutaneously q2w. Individuals from the active arm of the 1368.52 trial were given an initial intravenous placebo plus 600 mg pesonapront subcutaneously, followed by 600 mg pesonapront subcutaneously q2w.

[0269] Inclusion criteria:

[0270] Individuals will be enrolled (screened) into the trial at Visit 1 and will start treatment at Visit 2 if they meet the following criteria: • Male or female adult individuals 18 years of age or older • Written informed consent dated according to the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and local regulations prior to any screening procedures. • Moderate to severe hidradenitis suppurativa (HS) based on International Hidradenitis Suppurativa Severity Score System (IHS4) criteria, lasting at least 1 year prior to the baseline visit, as determined by the investigator through participant visit and / or medical history review. (If IHS4 score is not available, equivalent score based on HS-PGA or Hurley’s scoring system is acceptable based on documented investigator assessment) • HS lesions in at least 2 different anatomical areas (right / left inframammary, groin, subbreast, perineum) • Untreated with biologic or failure of TNF inhibitor (TNFi) for HS • Inadequate response to adequate course of oral antibiotics for HS in the past year according to investigator judgment. This does not apply to TNFi failure individuals. • Total abscess and inflammatory nodule (AN) count greater than or equal to 5. • Total draining fistula count less than or equal to 20. Other inclusion criteria apply.

[0271] Exclusion Criteria:

[0272] If any of the following criteria apply, the individual is not screened or treated: • Presence of active skin lesions other than HS that interfere with the assessment of HS. • Use of restricted medications: • Local corticosteroids to HS lesions within 1 week of Visit 2 • Systemic antibiotics within 4 weeks of Visit 2 • Use of systemic non-biologic immunomodulatory and / or immunosuppressive agents for HS within 4 weeks (or 5 half-lives, whichever is longer) of Visit 2. • Biologic agents used within 12 weeks or 5 half-lives (whichever is longer) prior to Visit 2. • Opioid analgesics within 2 weeks of Visit 2 • Live viral vaccines within 6 weeks of Visit 2 • Prior exposure to any immunosuppressive biologic agents other than TNFi for HS • Prior exposure to interleukin 36 receptor (IL-36R) inhibitors, including anakinra. • Treatment with any chemical or biological investigational device or investigational drug within a minimum of 30 days or 5 drug half-lives (whichever is longer) prior to Visit 2. • Pregnant, nursing, or planning to become pregnant at the time of the trial. Women who stop nursing prior to study drug administration are not required to be excluded from participation. • History of hypersensitivity / hypersensitivity reaction to the systemic administration of the trial agent or its excipients. • Patients with transplanted organs (>12 weeks prior to screening, corneal transplant excluded) or who have received stem cell therapy (e.g., Remestemcel-L). Other exclusion criteria apply.

[0273] Concurrent trial activities:

[0274] An overview of all relevant trial activities is shown in the flow chart Figure 4 ). The study week in the flow chart indicates the end of the respective week (e.g. end of week 1 = D8, end of week 2 = D15, end of week 3 = D22, end of week 4 = D29, etc.). The relevant activities are further described in the footnotes in the flow chart.

[0275] Days randomized / first intake of randomized study drug. If needed, some of the 2nd visit assessments (FN1) can be performed 2 days before or after the actual visit date after consultation with the sponsor. Individuals who prematurely discontinue trial treatment should have an EoT visit as soon as possible. All individuals not entering the OLE trial are expected to complete the EoT visit, the FUP1 visit (8 weeks after their last trial drug intake) and the final EoS visit (16 weeks after their last trial drug intake). For individuals entering the OLE trial at week 12, the EoT visit is their EoS visit in trial 1368-0052 (FN2 and see also FN 8 and FN16).

[0276] X c To indicate the time point of a complete physical examination. X t To indicate when the targeted physical examination is indicated (FN3). Vital signs are measured prior to blood sampling to avoid the influence of blood sampling on the vital measurements at all dosing visits. Additional assessments of vital signs (FN4) should be performed 10 minutes after subcutaneous and 5 minutes and 1 hour after intravenous administration of the study drug.

[0277] For women of childbearing potential, a serum pregnancy test is performed only at screening. A urine pregnancy test (FN5) is performed at all other visits indicated in the flow chart. Figure 4

[0278] Blood sampling for safety laboratories should be performed prior to study drug administration at the visit study drug administration. Preferably, but the individual does not have to fast for blood sampling for safety laboratories. If needed, the 2nd visit safety laboratory sample is allowed to be drawn within 48 hours prior to the actual visit date (FN 6).

[0279] Infection tests are performed at screening and at the EoT visit (FN 7).

[0280] Individuals who prematurely terminate the study drug should have an EoT visit as soon as possible. These individuals will have a FUP1 and EoS visit, 8 and 16 weeks after the last study drug administration, respectively (FN 8).

[0281] ​At the study drug administration study visit, pre-dose PK / ADA / NAb samples (FN9) are obtained approximately within 1 hour prior to the start of the intravenous infusion or subcutaneous injection. Deoxyribonucleic acid (DNA) reserve samples as appropriate. This sampling is possible only if the patient has signed a separate informed consent for this (FN10). Ultrasound lesion assessment is required and guided biopsy is performed at selected sites where ultrasound is available. At sites where ultrasound is not available, biopsy is performed without ultrasound guidance (FN11).

[0282] At screening, the C-SSRS baseline / screening scale will be completed. At all subsequent visits, the "since last visit" scale is completed (FN12).

[0283] At visits 4, 5, 6, 7, and 8, the individual will be given a two-week diary and an additional week of buffer time to obtain the remaining visit time window. The patient diary is used to obtain daily NRS scores, analgesic use, and other interventions to manage pain (FN13). The patient diary returned by the individual must be reviewed at the time of the patient visit to clarify any information at the time of the patient interview if needed (FN14).

[0284] Local tolerability at the site of administration of pesonovaptan is assessed by the investigator at the study drug administration visits and at the time of AE assessment by retrospective questioning since the last visit. Any observed local tolerability reactions (e.g., "swelling," "induration," "heat," "redness") should be reported as adverse events (FN15).

[0285] All individuals who complete study Week 12 can be enrolled in OLE study 1368-0067. These individuals do not need to complete the follow-up period and will have a study end visit at the EoT visit, coinciding with the first visit of 1368-0067 (FN16).

[0286] Demographics and relevant baseline efficacy parameters:

[0287] In both treatment groups, more females (overall: 59.6%) were randomized than males (overall: 40.4%), and the majority of individuals were White (overall: 67.3%), followed by Asian (overall: 11.5%) and unstated (overall: 11.5%). The mean (SD) age was 35.2 (11.1) years, and was comparable between the two treatment groups. The mean (SD) weight was 93.87 (23.18) kg; the minimum was 53.5 kg, and the maximum was 151.0 kg. The mean BMI (SD) was 32.28 (7.51) kg / m2in both treatment groups and was over 30 kg / m2, which is characteristic and expected in the HS patient population. Overall, 73.1% of individuals (n=38) were in the TNFi- naive population and 26.9% of individuals (n=14) were in the TNFi-failure population.

[0288] All individuals met the target inclusion criteria of moderate to severe HS. At baseline, a total of 80.8% of individuals (n=42) had severe HS according to IHS4, and 19.2% of individuals (n=10) had moderate HS. At baseline, a significant imbalance in the mean (SD) number of inflammatory nodules was observed in the treatment groups: secukinumab 9.5 (9.3), placebo 15.6 (12.2), while the mean abscess number and mean dT number were comparable between the treatment groups. Almost half of the individuals (n=24, 46.2%) had a total number of AN counts. Table 4. Demographics: If local laws did not allow collection of patient information, it was categorized as "unstated".

[0289] Primary outcome measure:

[0290] The primary efficacy endpoint in this trial was the percent change from baseline in total abscess and inflammatory nodule (AN) counts at Week 12.

[0291] Secondary outcome measures: a. Percent change from baseline in draining fistula counts at Week 12 [time frame: Baseline, Week 12] 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% in total AN count with no increase in abscess or draining fistula count from baseline (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 will be assessed at the time points mentioned in Table 6 (see also trial activity flowchart, Figure 4 . Achievement of clinical response or HiSCR is defined as a reduction of at least 50% in total AN count with no increase in abscess count from baseline and no increase in draining fistula count from baseline. c. Absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4) value at Week 12 [time frame: Baseline, Week 12]. IHS4 is an effective clinical scoring system for dynamic assessment of HS severity. Determination of IHS4 requires counting of nodules, abscesses, and draining fistula / sinuses, making it directly applicable 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). IHS4 will be assessed at the time points mentioned in Table 6 (see also trial activity flowchart, Figure 4). The HS severity was assessed in terms of absolute change from baseline or "IHS4" score and the resulting IHS4 score was achieved by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tubes. A total score of 3 or less indicates mild, 4-10 indicates moderate and 11 or higher indicates severe disease. d. Absolute change from baseline in the Hidradenitis Suppurativa Area and Severity Index (HASI) score at Week 12 [Time Frame: Baseline, Week 12]. The HASI model was developed after the Psoriasis Area and Severity Index (PASI). Four typical signs of HS-related inflammation (erythema, induration, open ulcer, and draining tube) were included. Each variable of the HASI for each predefined body region was scored on a Likert scale (0-3). For the BSA assessment, the number of palms involved for each body area (head, right axilla, left axilla, anterior chest, back, anterior bathing trunk, posterior bathing trunk, other) was assessed (one palm indicating 1% of the patient's BSA). This was converted to a percentage of the area. The area score was assigned to each area using the PASI method (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 4 clinical variable scores was multiplied by the area score for each involved region. This value was then multiplied by the proportion of the BSA of that region to give the local HASI score. The local HASI scores were added together to give the cumulative total HASI score (range 0-72). The HASI was assessed at the time points mentioned in Table 6 (see also trial activity flow chart, Figure 4 ). "HASI" combines the assessment of lesion severity and affected area into a single score ranging from 0 (no disease) to 72 (severe disease). e. Achievement of a Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) score of 0 or 1 at Week 12 [Time Frame: Week 1]. The HS-PGA instrument is a physician's assessment of a patient's HS at a specified time point. It scores the patient's disease severity as clear, minimal, mild, moderate to severe, or very severe based on 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 assessed at the time points mentioned in Table 6 (see also trial activity flow chart, Figure 4) "HS-PGA score" ranges from 0 to 5, where 0 (clear: no abscesses, draining tubes, inflammatory nodules, or non-inflammatory nodules), 1 (minimal: no abscesses, draining tubes, or inflammatory nodules and presence of non-inflammatory nodules), 2 (mild: no abscesses or draining tubes and 1-4 inflammatory nodules or 1 abscess or draining tube and no inflammatory nodules), 3 (moderate: no abscesses or draining tubes and > 5 inflammatory nodules or 1 abscess or draining tube and > 1 inflammatory nodule or 2-5 abscesses or draining tubes and < 10 inflammatory nodules), 4 (severe: 2-5 abscesses or draining tubes and > 10 inflammatory nodules), 5 (extremely severe: > 5 abscesses or draining tubes). f. At least 30% reduction in the Numerical Rating Scale (NRS30) for the patient's overall assessment of Hidradenitis Suppurativa (HS) pain relative to baseline at Week 12 [time frame: baseline, Week 12]. The HS pain NRS is an assessment indicator used in clinical trials to assess the severity of HS-related pain in individuals with HS. As it is a unidimensional measure of itch intensity and can be given daily with minimal patient burden. The recall period is 24 hours and responses are given on an 11-point scale ranging from 0 (no HS pain) to 10 (HS pain is unimaginable). The pain NRS is completed in a diary by the individual from screening through Week 12. g. Complete resolution of draining fistulae present at Week 12 [time frame: Week 12]. At least one episode (defined as an AN count increase of at least 25% from baseline with a minimum increase of 2) [time frame: up to Week 12] h. Absolute change in Dermatology Life Quality Index (DLQI) score from baseline at Week 12 [time frame: baseline, Week 12]. The DLQI is a quality of life questionnaire given to patients that contains ten questions covering six areas, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment (Table 5). The DLQI has a one-week recall period. Response categories include "not relevant" (score of 0), "not at all" (score of 0), "a little" (score of 1), "quite a lot" (score of 2), and "a great deal" (score of 3). Question 7 is a "yes" / "no" question with a "yes" score of 3. The total DLQI score is calculated by adding the scores of each question, resulting in a range of 0 to 30, where 0-1 = no impact on patient's life, 2-5 = minor impact, 6-10 = moderate impact, 11-20 = major impact, and 21-30 = very major impact on patient's life. The higher the score, the more severely impaired the quality of life. If one question is not answered, the question is scored as 0 and the total score is added as usual and indicated that the maximum score is 30; when only subscale scores are analyzed, the corresponding subscale score will be considered missing. If 2 or more questions are not answered (missing), the total DLQI score will be considered missing. A 4-point change from baseline is considered a clinically important difference. Table 5: The DLQI will be analysed under six headings as follows: Field Number of questions Score Symptoms and feelings Questions 1 and 2 Max 6 Daily activities Questions 3 and 4 Max 6 Leisure Questions 5 and 6 Max 6 Work and school Question 7 Max 3 Interpersonal relationships Questions 8 and 9 Max 6 Treatment Question 10 Max 3 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. i. Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at Week 12 [Time Frame: Baseline, Week 12]. "HiS-QoL" is a 17-item instrument given to patients to measure HS-specific quality of life in a clinical trial. The 17 HiS-QoL items include four symptom items, eight activity accommodation items, and five psychosocial items. Item scores are summed to yield a total score ranging from 0 to 68, where a higher score indicates a more severe impact on quality of life. j. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, The Functional Assessment of Chronic Illness Therapy (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): 81 1 -819) that assesses self-reported fatigue and its impact on daily activities and functioning. Answers are based on a 5-point Likert scale. Each question has "not at all," "a little bit," "somewhat," "quite a bit," and "extremely" and corresponds to scores of 0, 1, 2, 3, and 4, respectively (total score range: 0-52). The minimal clinically important difference (MCID) for change scores has been reported to be 3-4 points (Cella D, et al. 2005). The recall period for the items is 7 days. k. Patient Global Impression of Change (PGI-C), PGI-C is a 1 -item tool that assesses change in HS since starting study drug on a 5-point Likert scale. The tool is needed to anchor other instruments and assess pointers. l. Patient Global Impression of Severity (PGI-S), PGI-S is a 1 -item tool that assesses severity of HS in the last week on a 4-point Likert scale. The tool is needed to anchor other instruments and assess pointers. m. Incidence of treatment-emergent adverse events (TEAEs) [time frame: up to Week 16]. The intensity of adverse events was assessed by the investigator and graded according to the Rheumatology Common Toxicity Criteria (RCTC) version 2.0 developed by the Outcome Measures in Rheumatology (OMERACT) group (Woodworth T, Furst DE, Alten R, et al. Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J Rheumatol 2007;34(6): 1401-1414) see ISF for intensity / severity classification. Intensity options were: Grade 1 (mild: asymptomatic or transient, short duration <1 week); Grade 2 (moderate: symptomatic, duration of 1 to 2 weeks); Grade 3 (severe: long-term symptoms, reversible, major dysfunction) and Grade 4 (life-threatening: at risk of death, substantial dysfunction, especially in the permanent situation). Table 6: Overview of efficacy assessment indicators: • 1 Patients with baseline draining fistula count > 1 only • 2 Change from baseline • 3 Patients with baseline PGA score > 2 only • 4 DLQI improvement defined as reduction of > 4 points from baseline, for patients with baseline DLQI > 4 only

[0292] Adverse events

[0293] An AE is defined as any untoward medical occurrence in a patient, including worsening of a pre-existing condition, that arises from use of a medicinal product. The event does not necessarily have to be causally related to the treatment.

[0294] An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless of causality.

[0295] The following should also be recorded as AEs in the CRF and BIS SAE forms (if applicable): worsening of a potential disease or other pre-existing condition; changes in vital signs, ECGs, physical examinations, and laboratory test results (if they are judged to be clinically relevant by the investigator).

[0296] If such abnormalities exist prior to trial inclusion, they are considered as baseline conditions and should be collected only in electronic CRF (eCRF).

[0297] Serious adverse events

[0298] SAE is defined as any adverse event that results in death, immediate life-threatening, results in persistent or significant incapacity / disability, requires or prolongs inpatient hospitalization, is a congenital abnormality / birth defect, or is considered by the investigator to be serious for any other reason.

[0299] In accordance with the EMA initiative on important medical events, BI has developed a list of other AEs that by their nature can always be considered as "serious" even if they can not meet the criteria of SAE as defined above. AEs considered "always serious" include new histological cancers and worsening of existing cancers, which must be classified as serious events regardless of the duration of time between drug discontinuations and must be reported.

[0300] Causality of adverse events

[0301] Adverse events are judged in relation to the study product. The medical judgment used to determine the relationship must take into account all relevant factors, including consistency with known pharmacology of the drug or with known AEs of the drug class, temporal relationship, dechallenge or rechallenge, confounding factors such as concomitant medications, concomitant diseases and relevant medical history, lack of alternative explanations, indication of a dose response. The investigator is required to record "Yes" if, in the investigator's judgment, there is a reasonable possibility that the study product given caused the adverse event; or "No" if, in the investigator's judgment, there is not a reasonable possibility that the study product given caused the adverse event.

[0302] Adverse events of special interest (AESI)

[0303] The AESI pre-specified in the CTP is associated with any particular AE that has been identified at this program level as of particular interest for prospective safety monitoring and safety evaluation within this trial, for example, potential AEs based on knowledge of other compounds in the same class. The CTP specified AESI can be classified as serious or non-serious; all will be reported to the sponsor pharmacovigilance department in a fast manner (within the same timeframe as for SAEs) in the SAE form.

[0304] The following AESI are pre-specified: • Severe infections (graded according to RCTC): These include Pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-transplant lymphoproliferative disorder (EBV), progressive multifocal leukoencephalopathy, Bartonella disease (only disseminated), Blastomycosis, Toxoplasmosis, Coccidioidomycosis (only invasive), Candidiasis (invasive or pharyngeal), Cryptococcosis, other invasive fungi (white mycoses [zygomycosis, rhizopus, mucorales, lichtheimia], scedosporium / pseudallescheria boydii, fusarium), Legionellosis, Listeria monocytogenes (only invasive), Tuberculosis, Nocardiosis, Non-tuberculous mycobacteria, Salmonellosis (only invasive), HBV reactivation, Herpes simplex (only invasive), Shingles, Strongyloides (systemic infection syndrome and only disseminated form), Paracoccidioides, Penicillium marneffei, Sporothrix schenckii, Cryptosporidium species (only chronic), Microsporidiosis, Leishmaniasis (only visceral), Trypanosoma cruzi infection (Chagas disease) (only disseminated), Campylobacteriosis (only invasive), Shigellosis (only invasive), Vibrio disease (invasive due to V. vulnificus), HCV progression (Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis 2015;74:2107-2116). • Hepatic impairment: Hepatic impairment is defined by changes in the following liver laboratory parameters: • Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) elevation >3-fold ULN in combination with total bilirubin elevation >2-fold ULN measured in the same blood draw sample or in a sample drawn within 30 days of each other or • ALT and / or AST elevation >10-fold ULN. These laboratory findings constitute a liver impairment alert and any patient expressing these laboratory abnormalities needs to be followed according to the Drug Induced Liver Injury (DILI) checklist provided by the ISF. In case of clinical symptoms of liver impairment (jaundice, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant pain, etc.) without available laboratory results (ALT, AST, total bilirubin), the investigator should ensure that these parameters are analyzed, if necessary in an unscheduled blood test. User Defined AE Concept (UDAEC): Table 7. Definition of UDAEC

[0305] Treatment administered: Table 8. Test article ponesimod solution for infusion Table 9. Matching placebo solution for infusion of test product Table 10. Test article ponesimod solution for injection Table 11. Matching placebo solution for injection of test product

[0306] Individuals in the active arm receive a loading dose of 3600 mg ponesimod in 3 intravenous administrations of 1200 mg ponesimod each, once weekly (i.e. a total of three infusions for the loading dose will be administered at week 0, week 1 and week 2). Individuals in the placebo arm receive matching placebo intravenous administrations at the same scheduled time points. From week 4 to week 10, inclusive, individuals receive 1200 mg ponesimod or matching placebo in subcutaneous injections every two weeks (i.e. four injections are administered, for a total of 4 visits [1 injection per visit]).

[0307] This dose / regimen was chosen to optimize exposure of pesonalirab to assess its efficacy in individuals with HS. The intravenous loading dose was chosen to maximize the treatment response, duration of response, and earlier attainment of steady state. The loading dose is also able to initiate response earlier than 12 weeks. The intravenous loading dose, followed by a subcutaneous maintenance dose every 2 weeks. This dose is the maximum subcutaneous dose, which can be conveniently provided based on injection volume and number of injections Table 12: Doses and Dose Regimens

[0308] Results:

[0309] Primary Efficacy Outcome Analysis:

[0310] The key efficacy outcome was a significant positive signal for reduction in abscess count and draining fistula count at Week 12, consistent with the hypothesized mechanism of action of pesonalirab in HS. For the percent change from baseline in total abscess and inflammatory nodule (AN) count at Week 12, the difference in LS mean (95% Cl) observed between pesonalirab and placebo based on the pre-specified MMRM analysis was -4.1 (-31.7, 23.4). Due to small sample size, imbalance in baseline AN count between pesonalirab and placebo, and presence of extreme outliers in baseline AN count, an additional MMRM analysis was performed post-unblinding with a categorical effect of baseline AN count. The corresponding LS mean (95% Cl) between pesonalirab and placebo was -15.6 (-43.8, 12.6). For the percent change from baseline in draining fistula count at Week 12, the difference in LS mean (95% Cl) was -96.6 (-154.5, -38.8). See Table 13. Table 13: Percent (%) Change from Baseline in Total Abscess and Inflammatory Nodule (AN) Count at Week 12 - MMRM Estimates - SAF (EC-H MMRM) LS mean, difference, and confidence intervals were estimated by (REML)-based MMRM including a fixed categorical effect of treatment at each visit, prior use of TNF inhibitors, and a continuous effect of baseline at each visit and a random effect of individual. Primary estimate EC-H: Includes data up to use of rescue therapy for analysis and checks data post use. Uses unstructured covariance matrix.

[0311] Due to the small sample size, imbalance in baseline AN count between pasolizumab and placebo, and the presence of extreme outliers in baseline AN count, an additional MMRM analysis was performed post-unblinding with a categorical effect for baseline AN count. The corresponding LS mean (95% CI) between pasolizumab and placebo was -15.6 (-43.8, 12.6).

[0312] Secondary efficacy evaluation measures:

[0313] The continuous secondary evaluation measures at Week 12 were analyzed using the MMRM approach based on the estimation concept and model settings described for the primary evaluation measure. The binary secondary evaluation measures were evaluated descriptively by frequency table (with 95% confidence intervals) based on the safety analysis set (SAF). If needed, a logistic regression model at Week 12 for the binary evaluation measures was also applied. The model will include treatment and stratification factor (TNFi naive population versus TNFi failure population) as two categorical variables. As in the case of the primary estimate, any binary data collected after use of any rescue therapy will be examined and then imputed using the non- response imputation (NRI) approach.

[0314] The continuous other evaluation measures were evaluated in the same way as described for the primary evaluation measure. The binary other evaluation measures were evaluated in the same way as described for the secondary binary evaluation measures. For time to event evaluation measures, such as time to first achievement of HiSCR, Kaplan Meier estimates of survival / failure probabilities and median time to event were provided. 95% confidence intervals were provided. Questionnaires were summarized descriptively by visit.

[0315] Secondary evaluation measure: Achievement of HiSCR at Week 12

[0316] Hidradenitis Suppurativa Clinical Response (HiSCR) was defined as at least 50% reduction in total AN count with no increase in abscess count and no increase in dT count relative to baseline.

[0317] At Week 12, the proportion of individuals achieving HiSCR was numerically higher in the pasolizumab group compared to individuals in the placebo group; the difference in risk (95% CI) was 13.8 (-12.9, 33.9); see Table 14 below. Table 14: Proportion of patients achieving HiSCR at Week 12 - SAF (EC-H-NRI) Note: Percentages and proportions have denominator of number of patients in the analysis set. 95% CIs for each treatment were calculated by the Wilson method and 95% CIs for the treatment difference were calculated by the Chan and Zhang method. Primary estimate EC-H: Data up to the use of rescue therapy were included for analysis, and data after use were censored.

[0318] The consistency of treatment effect was investigated in the same predefined subgroups as the primary assessment. In general, the results for the secondary assessment proportion of patients achieving HiSCR at week 12 were similar across all subgroups. Patients presenting with dT at baseline showed a better HiSCR response in the pesolimumab group than in the placebo group. However, the treatment effect estimates were generally comparable to those in the primary analysis. Overall, given the small size of many subgroups, no evidence was found that pesolimumab had a different effect on the treatment of HS compared with placebo in all subgroups.

[0319] Secondary evaluation indicators: In addition to HiSCR

[0320] The primary analysis method for the secondary outcome measure was the estimated EC-H. However, any values ​​observed after the use of rescue medication for the purpose of disease exacerbation were censored according to the estimated EC, and no patients used rescue medication.

[0321] Continuous additional measures were assessed in the same manner as described for the primary measure. Binary additional measures were assessed in the same manner as described for the secondary binary measures. For time to event measures, such as time to first HiSCR, Kaplan-Meier estimates of the odds of survival / failure and median time to event were provided. 95% confidence intervals were provided. A descriptive summary of the questionnaire was provided by visit.

[0322] The results of additional secondary assessment indicators besides HiSCR are presented in Table 15.

[0323] Percent change in dT counts from baseline at week 12. At week 12, the pesolizumab group demonstrated greater clinical improvement compared to the placebo group; the LS mean (95% CI) difference compared to the placebo group was -96.6 (-154.5, -38.8); see Table 15 below. The reduction in dT counts in the pesolizumab group appeared to reach its near maximum as early as weeks 2 to 4 and appeared to be sustained through week 12.

[0324] Absolute change from baseline in IHS4 values ​​at Week 12: At Week 12, the pesotaxel group exhibited greater clinical improvement compared to the placebo group; the difference in LS mean (95% CI) was -13.9 (-25.6, -2.3) compared to the placebo group; see Table 15 below. Of note, the mean (SD) of the IHS4 value at baseline was 40.0 (34.2) in the placebo group and 28.2 (22.3) in the pesotaxel group.

[0325] Absolute change from baseline in HASI score at Week 12: At Week 12, the pesotaxel group exhibited greater clinical improvement compared to the placebo group; the difference in LS mean (95% CI) was -19.8 (-36.9, -2.7) compared to the placebo group; see Table 15 below. Of note, the mean (SD) of the HASI score at baseline was 82.1 (79.1) in the placebo group and 59.8 (49.5) in the pesotaxel group.

[0326] Achieved PGA score of 0 or 1 at Week 12: At Week 12, achieving a PGA score of 0 or 1 was observed in the pesotaxel group but not in the placebo group; the risk difference (95% CI) was 5.7 (-13.2, 18.6) compared to the placebo group; see Table 15 below.

[0327] Achieved NRS30 of patient’s global assessment of HS pain at Week 12: At Week 12, a higher proportion of individuals achieved NRS30 of patient’s global assessment of HS pain was observed in the pesotaxel group compared to the placebo group; the risk difference (95% CI) was 17.0 (-6.7, 33.8) compared to the placebo group; see Table 15 below.

[0328] Complete resolution of dTs at Week 12: At Week 12, a higher proportion of individuals achieved complete resolution of dTs was observed in the pesotaxel group compared to the placebo group; the risk difference (95% CI) was 18.3 (-7.9, 37.5) compared to the placebo group; see Table 15 below.

[0329] At least one flare (defined as an increase of at least 25% in AN count from baseline, with a minimum increase of 2) until Week 12: At Week 12, comparing the pesotaxel group to the placebo group for at least one flare, the risk difference (95% CI) was -9.1 (-33.1, 8.9); see Table 15 below.

[0330] Absolute change from baseline in DLQI score at Week 12: At Week 12, clinical improvement was similar in both treatment groups; the difference in LS mean (95% CI) was -0.1 (-4.4, 4.3) compared with placebo; see Table 15 below.

[0331] Absolute change from baseline in HiS-QoL total score at Week 12: At Week 12, clinical improvement was similar in both treatment groups; the difference in LS mean (95% CI) was 1.5 (-6.9, 9.8) compared with placebo; see Table 15 below. Table 15: Additional secondary endpoints other than HiSCR Notes: LS mean, difference, and confidence intervals were estimated by (REML)-based MMRM, including fixed categorical effects of treatment at each visit, prior use of TNF inhibitors, and continuous effects of baseline at each visit and random effects of individual. Primary estimate EC-H: included data up to use of rescue therapy for analysis, and examined data after use. Included only patients with baseline draining fistula >= 1. Used unstructured covariance matrix.

[0332] Other endpoints related to lesion counts included abscess, inflammatory nodule, noninflammatory nodule, and draining fistula counts

[0333] After Week 2, a greater proportion of individuals had at least 50% change from baseline in AN count in the secukinumab group compared with the placebo group. Starting at Week 4, values diverged between the two treatment groups. In the secukinumab group, the response rate increased to above 50% and the maximum response of 57.1% (20 patients) was seen at Week 6. This response content generally persisted until Week 12. At Week 12, 48.6% of patients (17 patients) in the secukinumab group and 35.3% of patients (6 patients) in the placebo group achieved at least 50% change from baseline in AN count.

[0334] The proportion of individuals with at least 75% change in AN count from baseline over time was measured based on the EN-H-NRI method (data not shown). The curves of the 2 treatment groups diverge starting at week 2. In the pesotaxizumab group, the response rate increases to 40% thereafter, with a maximum response of 40.0% (14 patients) seen at week 8, while the proportion of responders in the pesotaxizumab group is consistently higher than in the placebo group until week 10. Subsequently, the response rate decreases in the pesotaxizumab group, with similar responses seen in both treatment groups at week 12. At week 12, 25.7% of patients (9 patients) in the pesotaxizumab group and 29.4% of patients (5 patients) in the placebo group achieved at least 75% change in AN count from baseline.

[0335] The proportion of individuals with at least 90% change in AN count from baseline over time was measured based on the EN-H-NRI method. In general, a slightly higher proportion of patients in the pesotaxizumab group had at least 90% change in AN count from baseline over time compared to the placebo group.

[0336] The proportion of patients with at least 100% change in AN count from baseline over time was measured based on the EN-H-NRI method. In general, a slightly higher proportion of individuals in the pesotaxizumab group had at least 100% change in AN count from baseline over time compared to the placebo group. The responses in both treatment groups were similar to the occurrence of at least 90% change in AN count from baseline over time.

[0337] The proportion of individuals with complete elimination of dT up to week 12 was measured. After week 2, a greater proportion of individuals had complete elimination of dT in the pesotaxizumab group compared to the placebo group. The values of the 2 treatment groups diverge starting at week 2. In the pesotaxizumab group, the response rate increases to 32.1% (9 patients) at weeks 4 and 6. This response content decreases slightly to 25.0% (7 patients) at week 8 and continues up to week 12 thereafter.

[0338] The percent change in AN dT count from baseline up to week 12 was measured (data not shown). The curves of the 2 treatment groups diverge after week 1. In the pesotaxizumab group, the LS mean (95% CI) of the percent change in total AN dT count from baseline reaches -44.0 (-59.5, -28.5), while after week 1 to week 8, the response was greater in the pesomant group than in the placebo group. Subsequently, the response decreased in the pesomant group, with similar responses seen in both treatment groups at week 10. At week 12, the difference in the LS mean (95% CI) of the percent change from baseline in ANdT counts between the pesomant group and the placebo group was -8.8 (-32.3, 14.7).

[0339] The estimated probability of achieving a greater HiSCR in the pesomant group compared to the placebo group based on observed cases was measured (data not shown). The separation of the estimated probabilities between pesomant and placebo started 3 weeks after randomization and was maintained throughout the trial. The probability of achieving a response in the pesomant group started at week 1 and gradually increased to 71.4% by week 11. In the placebo group, the probability of achieving a response was 5.9% at week 1 and 47.1% at week 12.

[0340] The absolute change from baseline in IHS4 values until week 12 was measured. In the pesomant group, an improvement in IHS4 values was observed starting at week 1. In the pesomant group, the LS mean (95% CI) of the absolute change from baseline in IHS4 values was reached at -11.1 (-17.7, -4.5) at week 6, and the benefit in IHS4 values was sustained until week 12.

[0341] The proportion of patients with IHS4 categories over time was measured. At the OC estimate, the largest proportion of patients in the pesomant group had severe at baseline, 77.1% (27 / 35) of patients. At week 12, the largest proportion of patients were severe patients, 50.0% (15 / 30), and moderate patients, 40% (12 / 30), with a slight change in patient distribution over time to lower scores. In the placebo group, the largest proportion of patients had severe at baseline, 88.2% (15 / 17), and severe at week 12, 78.6% (11 / 14), with no change in patient distribution during the trial. The IHS4 categories in the pesomant group showed an improvement trend.

[0342] The absolute change from baseline in HASI scores until week 12 was measured. In the pesomant group, the HASI scores started to improve compared to the placebo group from week 2, reaching near-maximum effect by week 6. The benefit in HASI scores in the pesomant group was sustained until week 12.

[0343] Based on the observed, the estimated probability of achieving a PGA score of 0 or 1 was low and similar in both treatment groups. The separation in estimated probabilities between pesonalumab and placebo started 3 weeks after randomization, but the difference did not increase thereafter. In the pesonalumab group, the probability of an individual achieving a response was 5.7% (2 patients) by week 8 up to week 3, and 8.6% (3 patients) at week 12. In the placebo group, the probability of achieving a response was 5.9% (1 patient) at week 12, 9 weeks after randomization.

[0344] The proportion of patients with a PGA score of 0 or 1 over time was low in both treatment groups. The proportion of patients achieving a PGA score of 0 or 1 over time is presented in Figure 11.1.3.3:2. Under the EC-H-NRI estimate, the curves for pesonalumab and placebo did not separate.

[0345] A slightly higher proportion of patients in pesonalumab exhibited a reduction in PGA score of >2 points at week 12 compared to the placebo group. The proportion of patients with a reduction in PGA score of >2 points over time (patients with baseline PGA score >2 only) is presented in Figure 11.1.3.3:3. Under the EC-H-NRI estimate, the curves between pesonalumab and placebo exhibited the largest separation at week 6 compared to pesonalumab, but the difference decreased thereafter.

[0346] No patients used rescue therapy in either treatment group.

[0347] The proportion of patients achieving NRS 30 over time was measured (data not shown). Although the curves between pesonalumab and placebo separated from week 1 compared to pesonalumab and continued until week 12, the difference decreased over time from week 2 to week 4. The risk difference between pesonalumab and placebo was 22.9% at week 1, which was the maximum.

[0348] The absolute change from baseline in DLQI score was measured up to week 12. The mean and median DLQI score at baseline were similar between treatment groups. The mean absolute change from baseline in DLQI score decreased from week 1 and reached a maximum decrease of -2.8 at week 12 in both treatment groups.

[0349] Overall, the proportion of patients achieving a DLQI total score of 0 or 1 was low and similar between treatment groups.

[0350] The proportion of patients achieving improvement in DLQI was measured up to Week 12 (data not shown). Overall, the proportion of patients achieving improvement in DLQI was similar over the course of the trial. In both treatment groups, the proportion of patients achieving improvement in DLQI increased from Week 1. In the pesonalimab group, the proportion of patients achieving improvement in DLQI reached a maximum of 44.1% (15 patients) at Week 8 and continued up to Week 12. In the placebo group, the proportion of patients achieving improvement in DLQI gradually increased further after Week 1 up to Week 12, and reached a maximum of 46.7% (7 patients) at Week 12.

[0351] The absolute change from baseline in HiS-QoL total score up to Week 12 was similar in both treatment groups. In both treatment groups, the absolute change from baseline in HiS-QoL total score increased from Week 1 and reached a maximum at Week 8 (pesonalimab 6.8, placebo 6.1).

[0352] The FACIT-Fatigue score improved by 2.7 points in the pesonalimab group and by 3.7 points in the placebo group at Week 12. In the pesonalimab group, the improvement in FACIT-Fatigue score appeared to reach its closest maximum as early as Week 1 and appeared to continue up to Week 12. In the placebo group, the FACIT-Fatigue score worsened by 1.9 points at Week 1 and then improved up to Week 12, where an improvement of 3.7 points was seen. Details of the adjusted mean absolute change from baseline in FACIT-Fatigue score over time based on the EC-H-MMRM method were used for analysis (data not shown).

[0353] The proportion of patients with PGI-C score over time was measured. At OC estimates, in the pesonalimab group, the maximum proportion of patients was 68.8% (22 / 32) of patients with PGI-C score of 3 (no change) at Week 1 and 50.0% (15 / 30) of patients with PGI-C score of 2 (a little better) at Week 12, with the patient distribution changing over time to lower scores. In the placebo group, the maximum proportion of patients was 70.6% (12 / 17) of patients with PGI-C score of 3 (no change) at Week 1 and 50.0% (7 / 14) of patients with PGI-C score of 3 (no change) at Week 12, with no change in patient distribution during the course of the trial. PGI-C scores in the pesonalimab group showed a trend of improvement.

[0354] At baseline, the largest proportion of patients in the pesomplant group had a PGI-S score of 3 (severe) in 48.6% (17 / 35) of patients, while in the placebo group the largest proportion of patients had a PGI-S score of 2 (moderate) in 47.1% (8 / 17) of patients. At OC estimates, in the pesomplant group the largest proportion of patients had a PGI-C score of 3 (severe) at Week 1 in 46.9% (15 / 32) of patients and of 1 (moderate) at Week 12 in 37.9% (11 / 29), with patient distribution changing over time to lower scores. In the placebo group, the largest proportion of patients had a PGI-C score of 2 (moderate) at Week 1 in 56.3% (9 / 16) of patients and of 2 (moderate) at Week 12 in 50.0% (7 / 14) of patients, with no change in patient distribution over the course of the trial. PGI-S scores in the pesomplant group showed a trend toward improvement.

[0355] Safety

[0356] The proportion and incidence of patients with any AE was similar between placebo and pesomplant treatment groups. Four patients, five of whom, reported at least one AE (placebo: 14 patients, 87.5%; pesomplant: 28 patients, 77.8%). The incidence of drug-related AEs was higher in the pesomplant treatment group (15 patients, 41.7%) compared to the placebo treatment group (3 patients, 18.8%), largely due to injection site reactions. There were no occurrences of AEs leading to discontinuation of treatment, other notable AEs, and SAEs in the pesomplant group. In the placebo group, 1 patient (6.3%) each reported AEs leading to discontinuation of treatment, other notable AEs, and SAEs. No AEs leading to death, serious AEs, and particularly noteworthy protocol-defined AEs (systemic hypersensitivity reactions, including infusion reactions and anaphylaxis, severe infections [graded according to RCTC], opportunistic and Mycobacterium tuberculosis infections, or liver injury) were reported (Table 16). The proportion and incidence of patients with any AE was 65.4% at the loading period and 80.8% at the overall period. Table 16. Overview of AEs - Safety Analysis Set 1For safety reporting, patients randomized to receive placebo during the study were considered to be taking pesomplant in the pesomplant arm, not the assigned group. Patients taking pesomplant who were randomized to take placebo during the study were still considered to be in the pesomplant arm.2Systemic hypersensitivity reactions, including infusion reactions and anaphylaxis, severe infections [graded according to RCTC], opportunistic and Mycobacterium tuberculosis infections, or liver injury

[0357] The most frequently reported events across the entire period at the system organ class (SOC) level were infections and infestations, followed by general disorders and conditions, skin and subcutaneous tissue disorders, and nervous system disorders. The proportion of patients and incidence rates were generally balanced between the 2 treatment groups for most SOCs, with the exception of general disorders and conditions, and gastrointestinal disorders. The frequency and incidence rates of general disorders and conditions were lower in the placebo group (2 patients [12.5%]) compared with the pesotaxel group (12 patients [33.3%]) and also lower in gastrointestinal disorders; 1 patient [6.3%] in the placebo group compared with 6 patients [16.7%] in the pesotaxel group. All cases were classified as mild intensity. In terms of preferred term (PT) level, the most frequently reported AEs overall across the entire period were headache (Overall: 7 patients [13.5%]; pesotaxel: 4 patients [11.1%], placebo: 3 patients [18.8%]), followed by nasopharyngitis (Overall: 6 patients [11.5%]; pesotaxel: 3 patients [8.3%], placebo: 3 patients [18.8%]). All other PTs were reported for a total of at most 4 patients. In terms of PT level, the investigator-defined drug-related AEs that were reported more frequently in the pesotaxel group compared with the placebo group were nausea (pesotaxel: 2 patients [5.6%], placebo: 0 patients [0%]), acne (pesotaxel: 2 patients [5.6%], placebo: 0 patients [0%], injection site pain (pesotaxel: 3 patients [8.3%], placebo: 1 patient [6.3%]), injection site erythema (pesotaxel: 3 patients [8.3%], placebo: 0 patients [0%]), and fatigue (pesotaxel: 2 patients [5.6%], placebo: 0 patients [0%]). The incidence rates for other individual PTs were generally similar between the treatment groups. If no SMQ was available, the AE grouping by medical concept defined by the trial statistical analysis plan was based on either the standardized MedDRA query (SMQ) or the BI-customized systematic MedDRA query (BIcMQ). The AEs classified in the SMQs angioedema, depression (excluding suicide and self-harm), and suicide / self-harm were each reported for 1 patient, while 4 patients reported hypersensitivity. No meaningful numerical differences were identified between the treatment groups, given the smaller treatment group size and 2:1 randomization. No AEs classified in the SMQs anaphylactic reaction, opportunistic infections, severe infections, serious infections, malignant neoplasm, NMSC, and DRESS or in the BIcMQ tuberculosis infection were reported.

[0358] Anti-drug antibodies and neutralizing antibodies

[0359] Anti-drug antibody (ADA) responses were determined for each patient. The immunogenicity of pesotaximab was assessed using a multi-tiered approach. Briefly, all samples were first analyzed in an ADA screening assay, and only those samples found to be presumptively positive were evaluated in an ADA confirmation assay. Confirmed positive samples were then titrated (to obtain titer values). Neutralizing antibody (NAb) responses were also determined for each confirmed ADA-positive patient.

[0360] In total, 52 patients were randomized to receive pesotaximab or placebo (2: 1 ratio) in this trial. Thirty-five patients received pesotaximab at Week 0, and 17 patients received placebo at Week 0. Three patients in the pesotaximab treatment group and 1 patient in the placebo treatment group prematurely discontinued trial medication.

[0361] For ADA evaluation, baseline was defined as the trial visit day when the ADA sample was collected prior to initial pesotaximab treatment. Overall, of the 34 pesotaximab-treated ADA-evaluable patients, 6 patients (17.6%) were ADA-positive after treatment, and 27 patients (79.4%) were ADA-negative during the trial duration. The 6 ADA-positive patients after treatment were also ADA-positive at the last sample collected.

[0362] Most (66.7%) of the ADA-positive patients were also NAb-positive. In the ADA-positive HS patients, ADA was detected at a median onset time of 6.00 weeks and reached maximum titer at a median time of 12.0 weeks. Maximum titer occurred at the last sample collected. In the NAb-positive patients, NAb was detected at a median onset time of 7.90 weeks.

[0363] In the treatment-induced ADA-positive HS patients, ADA was detected at a median onset time of 6.00 weeks and reached maximum titer at a median time of 12.0 weeks. Maximum titer occurred at the last sample collected. In the NAb-positive patients, NAb was detected at a median onset time of 7.90 weeks.

[0364] Discussion

[0365] The pre-specified primary analysis of this smaller exploratory study yielded little difference between treatment groups in the percent change from baseline in the total count of abscesses and inflammatory nodules at Week 12. However, positive signals for secondary outcomes of clinical importance for HS were observed at Week 12: percent change from baseline in dT count, absolute change from baseline in IHS4 (dT, abscess, and inflammatory nodules counts), and absolute change from baseline in HASI (severity and extent of HS). Positive trends were also observed in patients achieving HiSCR and in patients achieving at least a 30% reduction in their overall assessment of HS pain by NRS from baseline.

[0366] The difference in LS mean (95% CI) in percent change from baseline in dT count at Week 12 was -96.6 (-154.5, -38.8). The difference in LS mean (95% CI) in absolute change from baseline in IHS4 values at Week 12 was -13.9 (-25.6, -2.3). The difference in LS mean (95% CI) in absolute change from baseline in HASI score was -19.8 (-36.9, -2.7). Although the assessment metrics containing inflammatory nodules exhibited lower efficacy, the HS-related outcomes including dT count, IHS4 values, and HASI score indicated improvement compared to secukinumab.

[0367] A higher proportion of patients achieved NRS30 in their overall assessment of HS pain was observed in the secukinumab group compared to the placebo group; the risk difference (95% CI) was 17.0 (-6.7, 33.8). Achievement of PGA score of 0 or 1 at Week 12 was observed in the secukinumab group but not in the placebo group. The numerical changes at Week 12 were similar 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.

[0368] Improvement trends were shown with secukinumab treatment up to Week 6 in percent change from baseline in both AN count and AN dT count, however the treatment effect was not maintained up to Week 12. The results of the HS-related assessment metrics including dT count, HiSCR, IHS4, and HASI indicated improvement compared to secukinumab, while the PGA-related assessment metrics did not exhibit efficacy of secukinumab during the course of the trial. The results of the subjective assessments including DLQI, HiS-QoL, and FACIT Fatigue did not exhibit efficacy of secukinumab, while the results related to NRS30, PGI-C, and PGI-S exhibited improvement trends in the secukinumab group compared to the placebo group.

[0369] Overall, in Trial 1368-0052, pesotaxel was well tolerated, generally consistent with what has been seen in previous pesotaxel trials in other indications. The results obtained in this clinical proof-of-concept study, in particular the unmet medical need (i.e., reduction in dT counts) consistent with the intended mechanism of action of pesotaxel in HS, support further development of pesotaxel in HS.

[0370] Analysis of an open-label study of pesotaxel following randomization to placebo control Phase Ila trial up to Week 50 in patients with moderate to severe HS:

[0371] Objective: To describe interim safety and efficacy results at 1 year under open-label pesotaxel treatment

[0372] Design: Phase Ila and OLE study design: At Week 24 (Week 12 of OLE), patients could have their dose of pesotaxel increased to 1200 mg SC q2w if necessary (based on responder status at the start of OLE and change in HS-PGA severity from the start of OLE). HS disease worsening was defined as a 150% increase in abscess and inflammatory nodule counts from baseline. Baseline refers to the last measurement prior to starting pesotaxel, i.e., the baseline of the Phase Ila trial in the previous pesotaxel arm or the baseline of the OLE study in the previous placebo arm Figure 8A ). Patients who met the inclusion criteria also had HS lesions in >2 different body regions; total abscess and inflammatory nodule (AN) count >5; total draining tube count <20; had not received biologic therapy or failed previous TNF-a inhibitor therapy for HS, and had an inadequate response to oral antibiotic therapy for HS in the past year Figure 8B .

[0373] Results: Pesotaxel was well tolerated through Week 50, with a safety profile consistent with the Phase Ila study and other pesotaxel trials. Safety analyses included patients who were treated with pesotaxel for >1 year (n=20) and those who prematurely discontinued treatment (n=25). Mean (SD) duration of exposure: 39.1 (24.1) weeks in the previous pesotaxel arm and 42.9 (28.4) weeks in the previous placebo arm.

[0374] All lesion counts continued to decrease. Continued improvement in HS severity and patient-reported outcomes was observed. Clinical benefit of pesotaxel was also observed in patients who switched from placebo (prior to OLE) to pesotaxel. Figures 9A-9DAbsolute change from baseline to Week 50 in lesion type and IHS4 score: The number of patients at baseline was n=30 for prior brodalumab and n=15 for prior placebo. For change from baseline, only patients with >1 relevant lesion type were included. The number of patients at Week 50 was n=15 for prior brodalumab and n=7 for prior placebo. Figure 9A Mean (95% CI) absolute change from baseline in draining tube count. Prior brodalumab group = -1.3 (-2.9, 0.3); prior placebo group = -3.7 (0.3, -7.8) (includes patients with >1 draining tube at baseline only). Figure 9B Mean (95% CI) absolute change from baseline in inflammatory nodule count. Prior brodalumab group = -3.7 (-7.9, 0.5); prior placebo group = -5.7 (-8.7, -2.8) (includes patients with >1 inflammatory nodule at baseline only). Figure 9C Mean (95% CI) absolute change from baseline in abscess count. Prior brodalumab group = -0.9 (-2.2, 0.5); prior placebo group = -2.4 (-7.6, 2.8) (includes patients with >1 abscess at baseline only). Figure 9D Mean (95% CI) absolute change from baseline in IHS4 score. Prior brodalumab group = -12.8 (-20.7, -5.0); prior placebo group = -23.4 (-50.8, 4.0).

[0375] Improvements in secondary and additional efficacy assessments continued through Week 50 are shown in Table 17 below. Table 17. Absolute change from baseline to Week 50 in secondary and additional assessments n Values are for Week 50; the number of patients at baseline was n=30 for prior brodalumab and n=15 for prior placebo. Includes only patients with >1 draining tube at baseline. Includes only patients with >1 abscess at baseline. § Includes only patients with a value of >1 on the patient's global assessment of HS pain on the NRS. CI, confidence interval; DLQI, Dermatology Life Quality Index; HASI, Hidradenitis Suppurativa Area and Severity Index; HiSCR, Hidradenitis Suppurativa Clinical Response; HiS-QOL, Hidradenitis Suppurativa Quality of Life; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Severity Score System; NRS, Numerical Rating Scale; OLE, open-label extension. Example 2: Phase IIb-III clinical trial: Treatment of patients with moderate-to-severe hidradenitis suppurativa

[0376] The following example is a continuation of the study described in Example 1.

[0377] Objectives: Study 1368-0098 consists of 2 parts: a dose-finding Phase IIb (Part 1) designed to find the optimal dose of pasotlimab in patients with moderate to severe HS for Phase III development; a confirmatory Phase III (Part 2) designed to evaluate the efficacy and safety of pasotlimab in patients with moderate to severe HS. The dose-finding phase (Part 1) will characterize the dose response curve and exposure response relationship and will support the identification of a dose of pasotlimab that provides the most benefit / risk to patients with moderate to severe HS by evaluating dosing regimens.

[0378] The primary objectives of the dose-finding phase are as follows: (1) To demonstrate a non-uniform dose response curve, based on the primary efficacy assessment of percent change from baseline in dT count at Week 8, to assess the magnitude of treatment effect and to assess the dose response relationship (2) To determine the optimal dose candidate for Part 2, by incorporating information on available safety and efficacy based on the primary efficacy assessment of percent change from baseline in dT count at Week 8

[0379] The secondary objectives of the dose-finding phase are as follows: (1) To demonstrate a non-uniform dose response curve based on selected secondary and other efficacy assessments at Week 8 (2) To assess the magnitude of treatment effect of percent change from baseline in dT count at Week 16 and the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4) value at Week 16. (3) To assess the persistence of pasotlimab efficacy up to Week 24 and up to Week 50. (4) To assess the safety of pasotlimab.

[0380] The objectives of the confirmatory phase are as follows:

[0381] The confirmatory phase is designed to provide substantial evidence of the efficacy, safety, and tolerability of pasotlimab compared to placebo in trial participants with moderate to severe HS.

[0382] The primary objective of the confirmatory phase (Part 2) is to demonstrate superiority of the mean percent change from baseline in dT count at Week 16 for one dosing regimen of pasotlimab (based on Part 1 analysis) versus placebo (for respective loading and maintenance doses).

[0383] The doses (loading dose and maintenance dose) for Part 2 (Phase III) are based on the primary analysis at the time the last trial participant completes Visit 10 (Week 8).

[0384] The secondary objectives are as follows: (1) To demonstrate superiority of pesonalumab over placebo for key secondary efficacy endpoints (2) To assess the safety of pesonalumab.

[0385] Overall design:

[0386] An international Phase IIb / III multicenter, double-blind, placebo-controlled, randomized trial evaluates the efficacy and safety of pesonalumab versus placebo in patients with moderate to severe HS. The primary efficacy endpoint, percent change from baseline in dT count at Week 8, and the secondary efficacy endpoint, percent change from baseline in dT count at Week 16, were selected based on the observed drug exposure versus response (reduction in dT counts) under the dosing regimen tested in Trials 1368-0052 and 1368-0067 (Example 1). Drain tubes are lesions that have a high impact on trial participants, and draining represents one of the most unmet needs. The pathophysiology of dTs suggests a potential key role for blocking IL36 receptor activation by pesonalumab. Based on efficacy results in Trial 1368-0052, the clinical results at Week 8 are early enough to evaluate the dose-exposure-response relationship for efficacy.

[0387] The absolute change from baseline in IHS4, HASI, and HiSCR values at Week 8 were selected to strengthen the dT count at Week 8 (primary efficacy endpoint for analysis).

[0388] Data from previous studies of pesonalumab in HS indicate the need for dose measurement distance from work and additional studies for the efficacy profile of this molecule in HS. The primary analysis is performed after all trial participants complete the Week 8 visit. In addition, the Week 16 interim analysis is performed after all trial participants complete the Week 16 visit. These two pre-specified analyses are instrumental in selecting the dosing regimen for Part 2 and in helping any needed adjustments to the primary and key secondary efficacy endpoints, sample size, and trial participant population. It is understood that based on modeling results, the loading / maintenance dosing regimen in Part 2 can differ from the dosing regimen tested up to Week 8 in Part 1, and is adjusted accordingly. For example, the amount and frequency of dosing can be adjusted based on observed response and defined primary and secondary efficacy endpoint measurements (e.g., potential benefits of the highest dosing regimen would be determined using the up to Week 8 data, if no benefits are exhibited, limiting the unnecessary exposure up to Week 16; and lower dose group trial participants can be titrated to higher doses according to the protocol based on clinical response).

[0389] Approximately 200 trial participants in Part 1 (Phase lib) and 260 trial participants in Part 2 (Phase III) were randomized. An overview of the trial design is presented in Figure 9A and 9B .

[0390] After signing the informed consent form, trial participants were screened for a period of up to 28 days and, if all eligibility criteria were met, were randomized to active groups (including high-, medium- and low-dose groups) or placebo group (50 trial participants in each group) in a 1 : 1 : 1 : 1 ratio. Randomization was stratified for TNFi status at baseline (TNFi naive population compared to TNFi exposed population) and dT counts (dT counts < 3; 4-10; > 10).

[0391] At least approximately 60 trial participants from the TNFi exposed population (this means 140 corresponding TNFi naive participants) and a maximum of approximately 100 trial participants from the TNFi exposed population (this means 100 corresponding TNFi naive participants) were randomized each. These participants previously exposed to TNFi can have experienced primary or secondary failure of TNFi treatment. Primary failure of TNFi treatment is defined as lack of efficacy after at least 3 months of treatment with an agent blocking TNF-alpha (patients who never responded), and secondary failure is defined as lack of clinical efficacy in trial participants who initially responded to an agent blocking TNF-alpha (patients who initially responded but subsequently relapsed). In addition, the TNFi exposed population can have stopped TNFi due to AEs or for other reasons.

[0392] Approximately 100 trial participants with baseline dT counts < 3 and 100 trial participants with baseline dT counts > 3 were planned to be randomized each.

[0393] Treatment Period

[0394] Once randomized, trial participants started a treatment period of 50 weeks. Administration of treatment will be until Week 48. Final assessment of treatment effect will be at Week 50 (EoT visit).

[0395] For the first four weeks, trial participants will be given an initial loading intravenous dose of pesonogliamab (1800 mg [high-dose group], 900 mg [medium-dose group] or 450 mg [low-dose group] weekly at Visit 2 [Week 0], at Visit 3 [Week 1], at Visit 4 [Week 2] and at Visit 5 [Week 3]) or matching placebo according to the assigned dose group.

[0396] From Visit 6 (Week 4) to Visit 9 (Week 7) (inclusive of endpoints), trial participants will be administered a weekly maintenance subcutaneous dose of pesonogliant (1200 mg [high dose group], 600 mg [moderate dose group], or 300 mg [low dose group] depending on the assigned dose group) or matching placebo. For trial participants who were initially randomized to the pesonogliant group, from Visit 10 (Week 8) to Visit 31 (Week 48) (inclusive of endpoints), trial participants will be administered a maintenance subcutaneous dose of pesonogliant: 1200 mg (high dose group and moderate dose group) or 600 mg (low dose group) subcutaneously every 2 weeks) depending on the assigned dose group.

[0397] From Visit 14 (Week 16), there is an option to increase the dose to the maximum subcutaneous dose of 1200 mg every two weeks (only applied blindly via IRT for low dose treatment group participants) if the dose has an inadequate clinical response defined as an increase of 25% in ANdT count compared to baseline and the investigator agrees to increase the dose.

[0398] For trial participants who were initially randomized to the placebo group, from Visit 10 (Week 8) to Visit 13 (Week 14) (inclusive of endpoints), participants will be administered matching placebo every 2 weeks; from Visit 14 (Week 16) to Visit 31 (Week 48) (inclusive of endpoints), participants will be switched to a subcutaneous dose of pesonogliant (starting with 3 loading subcutaneous doses of pesonogliant 1200 mg weekly and then maintenance subcutaneous dose of pesonogliant 1200 mg every 2 weeks).

[0399] From the ongoing Visit 23 (Week 32), trial participants will continue to receive the assigned dosing regimen or adjusted according to the primary analysis at Week 8, then the dosing regimen is adapted from Visit 23 (Week 32) onwards.

[0400] Trial participants who complete the EoT visit (Week 50) of the study and agree and meet the eligibility criteria for the OLE trial can continue to the OLE study. These trial participants do not need to complete the safety follow-up period and their EoT visit will also be considered their End of Study (EoS) visit, which is the first visit in the OLE trial.

[0401] Trial participants who permanently stop trial medication earlier than Visit 31 (Week 48) or are otherwise ineligible to enter the OLE trial will be invited to attend the EoT visit instead of the next scheduled visit and will then enter the safety follow-up period (16 weeks after the last dose).

[0402] Inclusion Criteria:

[0403] Part 1 (Phase lib)

[0404] Full age (at least > 18 years according to local regulations) on screening consent form.

[0405] Written informed consent according to ICH-GCP and local regulations signed and dated prior to allowing participation in the trial.

[0406] Based on IHS4 criteria, determined by the investigator through participant visit and / or review of medical history at least 6 months prior to baseline visit (including baseline visit), (if IHS4 score is not available prior to screening period, equivalent score based on HS-PGA or Hurley’s scoring system is acceptable based on documented investigator assessment)

[0407] Lesions of HS in at least 2 different anatomical regions (right / left axillae, right / left inguinal, right / left inframammary folds, intermammary region, right / left buttocks, perineum, other)

[0408] No prior biologic treatment or TNFi exposure for HS

[0409] For those not receiving biologic treatment, inadequate response to an adequate course of oral antibiotics for HS within the past 1 year prior to baseline visit according to investigator’s judgment.

[0410] Total AN count of greater than or equal to 5 at baseline visit

[0411] Total dT count of at least 1 at baseline visit.

[0412] Women of childbearing potential (WOCBP) must be compliant and capable of using highly effective birth control methods according to ICH M3(R2) with a lower failure rate of less than 1% per year when used consistently and correctly for the duration of the trial and for 16 weeks after the last dose.

[0413] Part 2 (Phase III)

[0414] The same inclusion criteria as for Part 1 (Phase IIb) will need to be met, except for potential criteria that will be identified after the primary analysis of the IIb phase results.

[0415] Exclusion criteria:

[0416] Part 1 (Phase IIb) a. Participants who must or wish to continue intake of restricted medications or any medication deemed likely to interfere with the safe conduct of the trial. b. Prior exposure to any immunosuppressive biologic agents for HS other than TNFi. c. Prior exposure to IL-36R inhibitors including risankizumab. d. Treatment with any investigational device or investigational drug of chemical or biological nature within a minimum of 30 days or 5 drug half-lives (whichever is longer) prior to Visit 2 (baseline visit). e. Females who are pregnant, breastfeeding, or planning to become pregnant at the time of the trial. Women who stop breastfeeding prior to study drug administration do not need to be excluded from participation. f. Participants with a history of hypersensitivity / hypersensitivity reactions to the systemic administration of the trial agent or its excipients. g. Participants with transplanted organs (>12 weeks prior to screening, corneal transplant excluded) or who have ever received stem cell therapy (e.g., Remestemcel-L). h. Participants with any documented active or suspected malignancy or history of malignancy within 5 years prior to the screening visit, with the exception of appropriately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. i. Participants with active or latent tuberculosis (TB) should be excluded. j. Participants with active systemic infection within 2 weeks of Visit 2 (baseline visit). These participants can be rescreened after completion of treatment for acute infection at the investigator’s discretion. k. Participants with relevant chronic infections as determined by the investigator, including human immunodeficiency virus (HIV) or viral hepatitis. Corresponding laboratory tests will be performed during screening. In the case of a positive hepatitis C antibody test, a positive reflex test of hepatitis C RNA PCR is considered positive. Patients can be rescreened if they are treated and cured from acute infection. l. Major surgery (as assessed by the investigator) within 12 weeks prior to the first study drug administration (Visit 2 - baseline visit) or planned during the study (e.g., hip replacement, aneurysm resection, gastric banding) m. Participants with severe, progressive, or uncontrolled liver disease defined as an increase in AST, ALT, or alkaline phosphatase >3 times the upper limit of normal (ULN) or total bilirubin >2 times the ULN at the screening visit and / or Visit 2 (baseline visit). Trial participants with Gilbert’s syndrome can be included unless the proportion of bilirubin fraction is not consistent with the diagnosis of Gilbert’s syndrome and unless total bilirubin is elevated >5 times the ULN at the screening visit. n. Participants with severe, progressive, or uncontrolled conditions at the time of screening such as renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurological, brain, psychiatric disorders (including a history of long-term alcohol or drug abuse or suspected abuse) or, except for HS, or signs and symptoms thereof that, in the investigator’s opinion, would compromise the safety or quality of the data and make the study participant unable to comply with the protocol to complete all study visits / procedures or complete the trial. o. Planned use of laser or other hair removal procedures on the area affected by HS during the trial period. p. Participants with any suicidal ideation of type 4 or 5 on the C-SSRS in the past 12 months prior to the screening visit (i.e., active suicidal ideation with method and intent but without specific plan, or active suicidal ideation with method, intent, and plan) q. Participants with any suicidal behavior in the past 2 years prior to the screening visit (i.e., actual attempt, interrupted attempt, failed attempt, or preparatory acts or behavior) r. Previous participation in this trial (Exception: trial participants re-screening) s. Presence of acute demyelinating polyneuropathy. t. Confirmed or suspected acute SARS CoV 2 infection. Participants who have recovered from SARS CoV 2 infection can be eligible: 14 days or more from the first appearance of symptoms or from the first PCR test confirmation and at least 14 days without SARS CoV 2 symptoms. If local criteria are more stringent, they will apply.

[0417] Part 2 (Phase III)

[0418] In addition to the potential criteria that will be confirmed after the analysis of the results of Phase lib, the same criteria as in Part 1 (Phase lib) will need to be met.

[0419] Related trial activities: see flowchart: Part 1 (Phase lib) Figure 11A &11B)

[0420] As illustrated in Figure 11A and 11B visits are marked corresponding to the week number of the visit and the ideal time window. Related activities are further described below as footnotes in the flowchart Figure 11A and 11B ).

[0421] For Visits 7, 9, 15, 20, 22, 24, 26, 28, and 30, trial participants will be offered the possibility of a home nursing visit, if locally permitted. In exceptional circumstances (i.e., epidemics, conflicts, etc.), visits may be conducted by telephone for safety information collection only. (FN1) Trial participants who discontinue trial treatment will have an end-of-treatment (EoT) visit as soon as possible. All trial participants not entering the open-label extension (OLE) trial are expected to complete an EoT visit and an EoS visit 16 weeks after their last dose of trial drug or 14 weeks from EoT. For trial participants entering the OLE trial at Week 50, the EoT visit will be the same as the EoS visit in their trial 1368-0098 (FN2, see also FNs 10 and 20).

[0422] X c Indicates the time when a complete physical examination will be given. X t Indicate when to administer a targeted physical exam (FN 3). Vital signs should be measured before blood sampling to avoid the influence of blood sampling on vital measurements at all dosing visits. Additional assessments of vital signs should be performed approximately 10 minutes after dosing for subcutaneous administration and approximately 5 minutes and 1 hour after dosing for intravenous administration (FN 4).

[0423] Females of childbearing potential should undergo a serum pregnancy test at Screening. A urine pregnancy test should be performed at all other visits as indicated in the flow chart. Figure 11A and 11B )(FN 5).

[0424] It is preferred, but not necessary, for trial participants to fast for blood sampling for the safety laboratory. This should be done before study drug administration (FN6) at the study drug administration visit.

[0425] Infection testing was performed at Screening and at the EoT visit (FN7).

[0426] ECG measurement precedes blood sampling and drug administration. ECG measurement is performed in the flow chart ( Figure 11A and Figure 11B Additional ECG measurements may be performed if the investigator deems it clinically indicated. (FN 8)

[0427] At the study visit for study drug administration, pre-dose PK / ADA / NAb samples will be obtained within approximately 2 hours prior to the start of the intravenous infusion or subcutaneous injection. At Week 0 / Week 1, post-dose PK samples will be obtained approximately 5 min after the end of the intravenous infusion (FN 9). Trial participants who prematurely discontinue study drug should have an EoT visit as soon as possible. These participants will subsequently have an EoS visit 16 weeks after the last study drug administration (FN 10).

[0428] Deoxyribonucleic acid (DNA) reserve samples as appropriate. This sampling is possible only if the trial participant consents by signing a separate informed consent form (FN 11). Skin biopsies are mandatory at selected sites and should be sampled under ultrasound (US) guidance. For all other sites, as appropriate (FN 12). US lesion assessment is mandatory at selected sites with US capability. For all other sites, as appropriate (FN 13).

[0429] IHS4 is used to classify trial participant severity at baseline. IHS4 will be derived from lesion counts by a trained healthcare professional (FN 14). Trial participants are provided with a trial participant diary with the goal of collecting daily information on NRS pain and pruritus disease from baseline until Visit 19 (Week 24). After Visit 19, NRS pain and NRS pruritus disease will be collected daily during the 7 days prior to the next scheduled visit (prior to Visit 23, Visit 27, Visit 31, and EoT visit). Site staff will collect the trial participant diary at the visit times indicated in the flow diagrams Figure 11A and 11B to assess pain and pruritus disease since the last visit (FN 15).

[0430] At screening, the C-SSRS baseline / screening scale will be completed. At all subsequent visits, the "since last visit" scale will be completed. (FN 16).

[0431] At Visit 2, the trial participants will be given paper copies of the Patient Diary Instructions. Site staff should be fully trained. Two copies of the weekly diary and one extra copy of the weekly diary will be given to the trial participant to obtain the remaining window of time for the visit. The diary will contain two scales, one for pruritus and one for pain. The trial participant diary will capture daily NRS pruritus and pain scores (and analgesic use, and other interventions to manage pain) until Visit 19. From Visit 23, the trial participant will record daily diary data for pain and pruritus for the last 7 days prior to the next scheduled visit (FN 17a). Once the electronic diary is available, the trial participant will be given instructions on how to use the electronic diary. The trial participant diary captures daily NRS scores in two scales, one for pruritus and one for pain, until Visit 19. From Visit 23, the trial participant will record data for pain and pruritus during the last 7 days prior to the applicable visit (last 7 days diary prior to the next scheduled visit). Analgesic use and other interventions to manage pain will be collected at the same time point, but in paper form (FN 17b). The trial participant must review the trial participant diary returned by the participant at the time of the trial participant visit so that any information can be clarified if needed at the time of the interview with the trial participant (if needed) (FN 18).

[0432] For local tolerability at the site of IMP administration, the investigator will assess by retrospective questioning since the last visit during study drug administration visits and at the time of AE assessment. Assess any observed local tolerability reactions (e.g. "swelling", "induration", "heat", "redness") and report as adverse events (FN 19).

[0433] All trial participants who complete Week 50 of the trial can be enrolled into the OLE trial. For these participants, the EoT visit will coincide with the EoS visit of Part 1 of Trial 1368-0098 and the first visit of the OLE trial. (FN 20).

[0434] Primary outcome measures:

[0435] Part 1 (Phase lib): Percent change from baseline in dT count at Week 8.

[0436] Part 2 (Phase III): Percent change from baseline in dT count at Week 16.

[0437] Secondary outcome measures:

[0438] Part I (Phase lib): a. Percent change from baseline in dT count at Week 16. b. Absolute change from baseline in IHS4 value at Week 8. c. Absolute change from baseline in IHS4 value at Week 16.

[0439] Part II (Phase III): a. Absolute change from baseline in IHS4 value at Week 16. b. Absolute change from baseline in Hidradenitis Suppurativa Area Severity Index (HASI) score at Week 16. c. Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR50) at Week 16: d. HiSCR50 is defined as at least 50% reduction in total abscess and inflammatory nodule (AN) count with no increase in abscess count and no increase in dT count from baseline. e. Percent change from baseline in abscess count at Week 16. f. Achievement of at least 50% reduction in dT count from baseline at Week 16. g. Achievement of at least 50% reduction in abscess and dT (AdT) count from baseline at Week 16. h. Achievement of at least 50% reduction in AN dT count from baseline at Week 16. i. Achievement of at least 30% reduction in Numerical Rating Scale (NRS30) of patients' global assessment of pain from HS at Week 16.

[0440] Other assessment endpoints:

[0441] Part I (Phase lib) efficacy:

[0442] Lesion count clinical assessment endpoints a. Percent change from baseline in dT count at each scheduled assessment. b. Achievement of at least 50% reduction in dT count from baseline at each scheduled assessment. c. Occurrence of complete resolution of dT at each scheduled assessment. d. Time to first occurrence of complete resolution of dT during the treatment period. e. Percent change from baseline in abscess count at each scheduled assessment. f. Achievement of at least 50% reduction in abscess count from baseline at each scheduled assessment. g. Occurrence of complete resolution of abscess at each scheduled assessment. h. Percent change from baseline in total AdT count at each scheduled assessment. i. Achievement of at least 50% reduction in AdT count from baseline at each scheduled assessment. j. Percent change from baseline in inflammatory nodule (N) count at each scheduled assessment. k. Percent change from baseline in total ANdT counts at each scheduled assessment. l. At least 50% reduction from baseline in ANdT counts achieved at each scheduled assessment.

[0443] Response, score, and seizure-related clinical assessment measures a. HiSCR50 achieved at each scheduled assessment. b. Absolute change from baseline in IHS4 value at each scheduled assessment. c. IHS4-55 response (defined as at least 55% reduction from baseline) achieved at each scheduled assessment. d. Absolute change from baseline in HASI score at each scheduled assessment. e. Physician Global Assessment (PGA) score of 0 or 1 achieved at each scheduled assessment. f. At least one HS flare present at each scheduled assessment: defined as at least 25% increase from baseline in AN counts, with a minimum increase of 2. g. Time to first occurrence of a HS flare during the treatment period.

[0444] Patient-reported outcomes (PROs) a. At least 30% reduction from baseline in numerical rating scale (NRS30) of patient’s global assessment of HS pain achieved at each scheduled assessment. b. Absolute change from baseline in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score at each scheduled assessment. c. Absolute change from baseline in FACIT-Fatigue Scale score at each scheduled assessment. d. Absolute change from baseline in Dermatology Life Quality Index (DLQI) score at each scheduled assessment. e. Absolute change from baseline over time in Patient Global Impression of Change (PGI-C) score; f. Absolute change from baseline over time in Patient Global Impression of Severity (PGI-S) score. g. Change from baseline in Hidradenitis Suppurativa Odor and Drainage Scale (HODS) at each scheduled assessment. h. Change from baseline in NRS Pruritus disease at each scheduled assessment. i. Change from baseline in Hospital Anxiety and Depression Scale (HADS) at each scheduled assessment;

[0445] Part 2 (Phase III): Efficacy a. HiSCR50 achieved at each scheduled assessment. b. Percent change from baseline in dT count at each scheduled assessment. c. At least 50% reduction from baseline in dT count achieved at each scheduled assessment. d. Complete resolution of dT at each scheduled assessment. e. Time to first complete resolution of dT during the treatment period. f. Percent change from baseline in abscess count at each scheduled assessment. g. At least 50% reduction from baseline in abscess count achieved at each scheduled assessment. h. Complete resolution of abscess at each scheduled assessment. i. Percent change from baseline in total AdT count at each scheduled assessment. j. At least 50% reduction from baseline in AdT count achieved at each scheduled assessment. k. Percent change from baseline in N count at each scheduled assessment. l. Absolute change from baseline in IHS4 value at each scheduled assessment. m. IHS4-55 response (defined as at least 55% reduction from baseline) achieved at each scheduled assessment. n. Absolute change from baseline in HASI score at each scheduled assessment. o. At least 30% reduction from baseline in patient's global assessment of HS pain on a numeric rating scale (NRS30) achieved at each scheduled assessment. p. Percent change from baseline in total ANdT count at each scheduled assessment. q. At least 50% reduction from baseline in ANdT count achieved at each scheduled assessment. r. PGA score of 0 or 1 achieved at each scheduled assessment. s. Absolute change from baseline in HiS-QoL total score at each scheduled assessment. t. Absolute change from baseline in FACIT-Fatigue scale score at each scheduled assessment. u. Absolute change from baseline in DLQI score at each scheduled assessment. v. Absolute change from baseline in PGI-C score over time. w. Absolute change from baseline in PGI-S score over time. x. Change from baseline in HODS at each scheduled assessment. y. Change from baseline in NRS pruritus score at each scheduled assessment. z. Change from baseline in HADS at each scheduled assessment. aa. At each scheduled assessment, at least one HS flare: defined as an increase of at least 25% in AN count from baseline with a minimum increase of 2. bb. Time to first occurrence of a HS flare during the treatment period. cc. Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS) - change from baseline in WPAI-HS. dd. EQ-5D-5L - change from baseline in EQ-5D. ee. Number of surgeries ff. Number of hospitalizations gg. Number of days not working / unemployed hh. Number of emergency room visits ii. Steroid-free time / Remission jj. Hormone therapy-free time (women) kk. Antibiotic-free time / Remission

[0446] Adverse events; see discussion in Example I above.

[0447] Treatment administered Table 18. Test article ponesimod solution for infusion Table 19. Matching placebo solution for infusion of test product Table 20. Test product ponesimod solution for injection Table 21. Matching placebo solution for injection of test product Substance: Placebo matching with pesotrilumab Pharmaceutical formulation: Solution for injection Unit concentration: Vial with a fill volume of 2 mL Route of administration: Subcutaneous injection Dosimetry: See Tables 19 to 22 below. Table 22: Placebo-controlled dosing treatment period Part I (up to Visit 14 (Week 16)) Wk = number of weeks (study weeks), i.v. = intravenous, s.c. = subcutaneous, P = placebo

[0448] Part 1 (Phase lib)

[0449] Ponesimod test group, up to Visit 14 (Week 16): a. High dose group (1800 mg i.v. qw x 4, 1200 mg s.c. qw x 4 [through and including visit 9 (week 7)], followed by 1200 mg s.c. q2w, through visit 14 [week 16]) b. Medium dose group (900 mg i.v. qw x 4, 600 mg s.c. qw x 4 [through and including visit 9 (week 7)], followed by 1200 mg s.c. q2w, through visit 14 [week 16]) c. Low dose group (450 mg i.v. qw x 4, 300 mg s.c. qw x 4 [through and including visit 10 (week 8)], followed by 600 mg s.c. q2w, through visit 14 [week 16])

[0450] Placebo group: a. Matched through and including visit 14 (week 16) b. From visit 14 (week 16), trial participants in the placebo group will be switched to 1200 mg s.c. q2w, through visit 23 (week 32), starting with a loading dose of 3600 mg s.c. loading dose of pesotaximab (1200 mg s.c. qw x 3) c. From visit 23 (week 32), trial participants will continue to receive the dosing regimen previously assigned until the primary analysis results (week 8) are available. Upon availability of the primary analysis efficacy and safety results, the dosing regimen can be adapted from visit 23 (week 32) onwards by amendment.

[0451] Treatment administration will continue through week 48. Final assessment of treatment effect will be at week 50 (EoT visit). Table 23: Overview of treatment course from visit 15 (week 17) through visit 31 (week 48) Wk = week number (study weeks), s.c. = subcutaneous, P = placebo

[0452] Pesotaximab test groups, from visit 14 (week 16) to visit 23 (week 32) a. From visit 14 (week 16), trial participants in the high dose group and medium dose group will receive 1200 mg s.c. q2w, through visit 23 (week 32). b. From visit 14 (week 16), trial participants in the low dose group will receive 600 mg s.c. q2w, through visit 23 (week 32). c. Escalation to 1200 mg q2w from 600 mg q2w will be possible (low dose cohort) based on inadequate clinical response according to the protocol, if applicable.

[0453] From Visit 23 (Week 32), trial participants continue to receive the previously assigned dosing regimen until the primary analysis (Week 8). Based on the primary analysis efficacy and safety results, the dosing regimen can be adapted from Visit 23 (Week 32).

[0454] Placebo: a. Matched until Week 16. b. From Week 16, trial participants in the placebo group will be switched to the selected dosing regimen based on Phase IIb.

[0455] Treatment administration will continue until Week 50. The final assessment of treatment effect will be at Week 52 (EoT visit). Table 24: Doses and treatment schedule for the intravenous loading phase Table 25: Doses and treatment schedule for the subcutaneous phase

[0456] Results:

[0457] Results of efficacy from HS lesion counts include the primary assessment proposed for Part 1 and Part 2; percent change from baseline in dT counts. Flowing pus / fistula / sinus should only be considered a dT when draining. Other efficacy results from lesion counts are % change from baseline in each type of lesion or combination thereof, IHS4, and HiSCR50. HASI is derived from detailed clinical assessment of the extent and intensity of HS lesions according to specific criteria.

[0458] HS-PGA is a simple global clinical assessment.

[0459] In this study, efficacy is assessed according to patient-reported outcomes including skin pain, pruritus, and draining and odor, Dermatology Life Quality Index, assessment of HiS-QoL.

[0460] The description of the specific scores, indices, or PROs used as efficacy outcomes are previously described in the definition and description of the Phase IIa trial in Example 1, specifically the following: International Hidradenitis Suppurativa Severity Score System (IHS4), Hidradenitis Suppurativa Clinical Response (HiSCR50), Hidradenitis Suppurativa Area and Severity Index (HASI), Hidradenitis Suppurativa Physician Global Assessment (HS-PGA), Numerical Rating Scale for Pain (NRS Pain), Dermatology Life Quality Index (DLQI), Hidradenitis Suppurativa Quality of Life (HiS-QoL), Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue), Patient Global Change Impression (PGI-C), and Patient Global Severity Impression (PGI-S).

[0461] Additional instruments included the Itch Numerical Rating Scale (NRS Itch), Hospital Anxiety and Depression Scale (HADS), and Hidradenitis Suppurativa Odor and Drainage Scale (HODS) described below.

[0462] Itch Numerical Rating Scale (NRS Itch): The HS Itch NRS is an assessment indicator used to assess the severity of HS-related itch in patients with HS in a clinical trial. The Patient Global Assessment of HS Itch assesses the worst HS Itch. Ratings range from 0 (no itch) to 10 (worst imaginable itch). It is a unidimensional measure of itch intensity and can be given daily with minimal burden to the trial participant. The recall period is 24 h and responses are given on an 11-point scale ranging from 0 (“no itch”) to 10 (“worst imaginable itch”). The trial participant is asked to rate their itch intensity using this scale.

[0463] Hidradenitis Suppurativa Odor and Drainage Scale (HODS): The HODS is an 8-item scale developed to assess patients’ HS-related drainage and odor. It covers two domains: drainage (5 items) and odor (3 items). Response options range from 1 to 5. Higher scores depict worse outcomes for the concept being assessed.

[0464] Hospital Anxiety and Depression Scale (HADS): The HADS is an instrument used to screen for anxiety and depression in non-psychiatric populations. The HADS consists of 14 items, 7 each for anxiety and depressive symptoms; possible scores for the subscales range from 0 to 21.

[0465] Additional instruments included in Part 2 (Phase III) include only the Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) described below.

[0466] Work Productivity and Activity Impairment Questionnaire for HS (WPAI-HS): The WPAI-HS is a 6-item instrument to assess the impact of HS on the ability to work and perform normal daily activities.

[0467] EuroQol 5-Dimensions 5-Level (EQ-5D-5L): The EuroQoL-5D-5L was used to assess changes in quality of life. The descriptive system contains five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, with the pointer labeled "best possible health" and "worst possible health."

[0468] Statistical Methods:

[0469] Part I (Phase lib)

[0470] The primary analysis of the primary efficacy measure consisted of a combination of the MCPMod-based test for non-parallel dose response curves and the assessment of the quantitative treatment benefit.

[0471] To account for the repeated nature of the data and the covariates in the model, an MMRM analysis based on the MCPMod analysis will be performed.

[0472] The percent change from baseline in dT counts will be used as the response variable for the MMRM. The MMRM will include a fixed categorical effect of treatment at each visit, TNFi status at baseline, and categorical baseline dT counts at each visit. Visits will be handled as unstructured covariates for the modeling of within-patient measurements in a repeated measures fashion.

[0473] Part 2 (Phase III)

[0474] The primary efficacy measure was the percent 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 the adjusted means for treatment effects. This model will include a fixed effect of treatment category at each visit, TNFi status at baseline, and categorical baseline dT counts at each visit. The primary treatment comparisons will be contrasts between treatments at Week 16.

[0475] Significance testing will be based on adjusted treatment differences using a one-sided alpha of 0.025.

[0476] Safety:

[0477] Safety will be assessed descriptively based on the following observations and examination results described in previous Example I: physical examination, vital signs, clinical laboratory values (hematology, clinical chemistry methods, coagulation, infection tests, and urinalysis), 12-lead ECG, AEs, serious AEs (SAEs), AE intensity assessed by CTCAE version 5.0, and suicidality. Physical examinations will be performed at the time points specified in the flow chart Figure 11A and 11B

[0478] Part I and II: Incidence of treatment-emergent adverse events (TEAEs)

[0479] Other objectives:

[0480] Other objectives assess other measures of efficacy, including magnitude of effect up to Week 16, pharmacokinetics (PK), immunogenicity of pesanilumab (anti-drug antibodies [ADA] and neutralizing antibodies [NAb]), and exploratory biomarkers related to HS changes and IL36 pathway post-treatment (assessment of gene expression in skin biopsies and whole blood, assessment of serum proteomics, and imaging markers acquired by ultrasound [US]).

[0481] Discussion

[0482] The primary objectives of the dose-finding phase are to confirm a non-uniform dose response curve, to assess the quantitative treatment magnitude of effect, and to assess the dose-response relationship based on the primary efficacy measure of the percent change from baseline in dT counts at Week 8. In addition, the dose-finding phase is used to determine the optimal dose for Part 2 by incorporating available safety and efficacy information based on the primary efficacy measure of the percent change from baseline in dT counts at Week 8. Efficacy of pesanilumab is assessed based on the percent change from baseline in dT counts at Weeks 8 and 16; absolute change from baseline in IHS4 values at Week 8; and absolute change from baseline in IHS4 values at Week 16.

[0483] Key secondary efficacy measures can be used to demonstrate efficacy, including: assessment of absolute change from baseline in IHS4 values at Week 16; absolute change from baseline in Hidradenitis Suppurativa Area Severity Index (HASI) score at Week 16; achievement of hidradenitis suppurativa clinical response (HiSCR50) at Week 16; percent change from baseline in abscess count at Week 16; achievement of at least 50% reduction from baseline in dT counts at Week 16; achievement of at least 50% reduction from baseline in abscess and dT (AdT) counts at Week 16; achievement of at least 50% reduction from baseline in ANdT counts at Week 16; and achievement of at least 30% reduction from baseline in numerical rating scale (NRS30) of patients’ overall assessment of pain from HS at Week 16.​

[0484] Secondary objectives are to demonstrate non-uniform dose response curves for secondary and other efficacy assessment endpoints selected based on week; to assess the quantitative treatment effect size of the percent change from baseline in dT counts at Week 16 and the absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4) value at Week 16; to assess the durability of the efficacy of pesonolisantil up to Week 24 and up to Week 50; and to assess the safety of pesonolisantil.

[0485] The primary objective of the confirmation phase is to demonstrate superiority of the mean percent change from baseline in dT counts at Week 16 for one dosing regimen (loading and maintenance doses) of pesonolisantil relative to placebo, identified based on analysis of Phase lib data.

[0486] While certain aspects and embodiments of the present application have been described, these have been presented by way of example only, and are not intended to limit the scope of the application. Indeed, the novel methods and systems described herein can be embodied in a variety of other forms. The following claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the application.

[0487] All patents and / or publications, including journal articles, cited herein are expressly incorporated herein by reference for the purpose of describing and disclosing, by way of example only, the various substances described therein that might be used with the present application.

Claims

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

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

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

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

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

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

7. The method of any one of the preceding claims, 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: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); 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); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); 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); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); 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); the amino acid sequence of SEQ ID NO:44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO:53 (H-CDR1); the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO:72 (H-CDR3); 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); the amino acid sequence of SEQ ID NO:44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO:53 (H-CDR1); the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO:72 (H-CDR3); 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); the amino acid sequence of SEQ ID NO:44 (L-CDR3); and b) a heavy chain variable region comprising: the amino acid sequence of SEQ ID NO:53 (H-CDR1); the amino acid sequence of SEQ ID NO:62, 108, 109, 110, or 111 (H-CDR2); the amino acid sequence of SEQ ID NO:72 (H-CDR3).

8. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises: 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.

9. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises: 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.

10. The method of any one of the preceding claims, wherein the anti-IL36-R antibody or antigen binding portion thereof is spesolimab.

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

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

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

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

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

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

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

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

19. The method of any of the preceding claims, wherein 2, 3, or 4 intravenous or subcutaneous loading doses are administered at a time interval of qw, q2w, q4w.

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

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

22. The method of claim 20, wherein the maintenance dose of the anti-IL-36R antibody is delivered subcutaneously qw, q2w, or q4w at week 4, week 5, week 6, and / or week 7 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 individual once every two weeks after the last dose of the maintenance dosing period and / or after week 8.

24. The method of any of the preceding claims, wherein the administration results in one or more of the following efficacy assessment indicators: a) percent change from baseline in dT count at week 8 and / or week 16; b) absolute change from baseline in IHS4 score 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) percent change from baseline in abscess count at week 16; f) achievement of at least 50% reduction in dT count from baseline at week 16; g) at least a 50% reduction in abscess and dT (AdT) count from baseline at Week 16; h) at least a 50% reduction in AN dT count from baseline at Week 16; i) at least a 30% reduction in the patient's Numerical Rating Scale for the global assessment of HS pain (NRS30) from baseline at Week 16; j) the percent change in dT count from baseline at each scheduled assessment; k) at least a 50% reduction in dT count from baseline at each scheduled assessment; l) complete resolution of dT at each scheduled assessment; m) the time to first occurrence of complete resolution of dT during treatment; n) the percent change in abscess count from baseline at each scheduled assessment; o) at least a 50% reduction in abscess count from baseline at each scheduled assessment; p) complete resolution of abscess at each scheduled assessment; q) the percent change in total AdT count from baseline at each scheduled assessment; r) at least a 50% reduction in AdT count from baseline at each scheduled assessment; s) the percent change in inflammatory nodules (N) count from baseline at each scheduled assessment; t) at least a 30% reduction in the patient's Numerical Rating Scale for the global assessment of HS pain (NRS30) from baseline at each scheduled assessment; u) the absolute change in Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score from baseline at each scheduled assessment; v) the absolute change in FACIT-Fatigue scale score from baseline at each scheduled assessment; w) the absolute change in Dermatology Life Quality Index (DLQI) score from baseline at each scheduled assessment; x) the absolute change in Patient Change Global Impression (PGI-C) score over time from baseline; y) the absolute change in Patient Severity Global Impression (PGI-S) score over time from baseline; z) the change in Hidradenitis Suppurativa Odor and Drainage Scale (HODS) from baseline at each scheduled assessment; aa) the change in NRS pruritis from baseline at each scheduled assessment; bb) the change in Hospital Anxiety and Depression Scale (HADS) from baseline at each scheduled assessment; cc) the percent change in total AN dT count from baseline at each scheduled assessment; or dd) at least a 50% reduction in AN dT count from baseline at each scheduled assessment.

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

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

27. 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 of any of the preceding claims, the method comprising administering to the patient an effective amount of the anti-IL-36R antibody in one or more intravenous or subcutaneous doses, wherein the HS symptoms comprise inflammatory lesions, abscesses, draining fistulae / sinuses or tunnels (dTs), HS-associated inflammation (erythema, induration, open ulcers), HS-associated infection, and / or HS-associated pain.

28. The method of any of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients achieve a clinical response at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by the Hidradenitis Suppurativa Clinical Response Score (HiSCR), defined as a reduction of at least 50% in total AN count from baseline with no increase in abscess or draining fistula count.

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

30. The method of any of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients show a significant clinical improvement in terms of flares at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, wherein a flare is defined as an increase of at least 25% and a minimum increase of 2 in AN count from baseline total AN count.

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

32. The method of any of claims 25-27, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients show complete resolution of dTs at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment.

33. 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 at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by an absolute change from baseline in the International Hidradenitis Suppurativa Severity Score System (IHS4).

34. 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 at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by an absolute change from baseline in the Hidradenitis Suppurativa Area and Severity Index (HASI).

35. 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 a 30% reduction in the Patient's Global Assessment Numerical Rating Scale of HS Pain (NRS30) at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, relative to baseline.

36. 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 a score of 0 or 1 as measured by Physician Global Assessment (PGA) at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, relative to baseline.

37. 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 clinical improvement at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by an absolute change from baseline in the Dermatology Life Quality Index (DLQI) score.

38. 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 clinical improvement at week 8, week 12, week 16, week 20, week 24, week 36, week 48, week 52, week 60, or week 72 of the treatment, as measured by an absolute change from baseline in the Hidradenitis Suppurativa Quality of Life (HiS-QoL) total score.

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

40. The method of claim 39, wherein one, two, three, or four intravenous doses of the anti-IL-36R antibody is followed by one, two, three, or four subcutaneous doses of the anti-IL-36R antibody.

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

42. 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 comprising 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 the anti-IL-36R antibody of any one of the preceding claims.

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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