Methods for Treating Generalized Pustular Psoriasis

Abstract

The present invention relates to the treatment or alleviation of signs and symptoms of generalized pustular psoriasis (GPP) or acute flare-ups of GPP with anti-IL-36R antibodies.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing, which has been submitted via EFS-Web in ASCII format, which is incorporated herein by reference in its entirety. Said ASCII copy, created on January 31, 2022, is named 09-0719-WO-1-2022-03-03-SL.txt and is 147,456 bytes in size.

[0002] TECHNICAL FIELD OF THEINVENTION The present invention relates to the use of anti-IL-36R antibodies in methods and compositions for the treatment of patients with generalized pustular psoriasis (GPP). More specifically, the present invention relates to the treatment of GPP or GPP flare in a patient by administering two 900 mg intravenous (iv) doses of anti-IL-36R antibodies to the patient; the second dose being administered less than two weeks after the first dose. More specifically, the present invention relates to the treatment of GPP in a patient by administering one 900 mg intravenous dose of spesolimab to the patient, and if symptoms of GPP persist, an additional 900 mg intravenous dose is administered one week after the first dose.

[0003] background GPP is a severe skin disease characterized by repeated acute flares caused by systemic inflammation affecting the skin and internal organs. The classical presentation of acute GPP was first described by von Zumbusch in 1909 as recurrent pustular psoriasis. Although GPP and plaque psoriasis can occur simultaneously in individual patients, GPP differs from plaque psoriasis in clinical symptoms, pathophysiology, histopathology, response to therapy, epidemiology, and genetics.

[0004] Therefore, it is very important to distinguish GPP from plaque psoriasis or erythrodermic psoriasis with secondary pustulation. The clinical presentation of GPP is quite different from psoriasis vulgaris (PV) in its episodic nature, with normal skin often appearing between very acute and severe disease flares. GPP is clinically characterized by a preponderance of pustules as the primary lesions on an erythematous base, rather than red plaques covered with silvery white scales, which represent the primary lesions of typical plaque psoriasis. In addition, the histopathological hallmark of GPP is the well-defined spongiform pustules located in the substratum corneum of the epidermis. GPP may be accompanied by systemic symptoms (fever, elevated C-reactive protein, and neutrophilia) and severe extracutaneous organ manifestations (liver failure, renal failure, CV shock). Patients with GPP may have preexisting or coexisting psoriasis vulgaris, but it is possible to clinically distinguish patients with predominantly plaque-type disease with a secondary pustular component (psoriasis vulgaris) from patients with predominantly pustular disease with a concomitant plaque component (GPP) based on the constellation of signs (the predominant lesions are pustules rather than plaques) and the localization of GPP pustules on an erythematous base rather than a psoriatic plaque.

[0005] Because the description of GPP is not consistent among standard dermatology textbooks, the European Rare and Severe Psoriasis Expert Network (ERASPEN) has defined consensus criteria as key diagnostic criteria for acute GPP, including the presence of primary, sterile, macroscopically visible pustules on nonacral skin (excluding cases in which pustules are confined to psoriatic plaques) with or without systemic inflammation, with or without plaque-type psoriasis, and either recurrent (more than one episode) or persistent (more than 3 months).

[0006] Chronic GPP represents a state between flares of the disease that may be characterized by complete disappearance of symptoms, or the persistence of residual skin symptoms such as erythema and scaling and a few pustules.

[0007] Current treatment options for controlling acute GPP and subcutaneous responses are limited and do not provide sustained efficacy. There are currently no approved treatments for GPP in the United States and Europe, but retinoids, cyclosporine, or methotrexate are recommended. Although these treatments have been described as "markedly effective or effective" in 70-84% of patients (J Am Acad Dermatol. 2012;67(2):279-88), these data are based on a retrospective cohort study from Japan that did not include clearly defined endpoints (Japanese Journal of Dermatology. 2010;120(4):815-39). Furthermore, these treatments cannot be used long-term due to side effects and contraindications (retinoids: teratogenicity, alopecia; cyclosporine: excessive hair growth, nephrotoxicity; methotrexate: hepatotoxicity).

[0008] Biological agents (mostly TNF (tumor necrosis factor) inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used for the treatment of patients with more severe, widespread or treatment-resistant GPP based on a small number of published case series. However, these drugs are also associated with limitations in efficacy (frequently with incomplete and delayed responses) and safety as well as contraindications (infusion reactions, tuberculosis, cardiovascular disease). Thus, there is a need in the art for novel targeted therapies for the treatment and / or prevention of GPP.

[0009] Summary of the Invention The present invention addresses the above needs by providing biologics, particularly antibodies that bind to IL-36R, to provide therapeutic or prophylactic treatment of GPP, including acute GPP and associated signs and symptoms, such as GPP flares.

[0010] In one embodiment, the present invention relates to the treatment of GPP in a patient by administering to the patient two 900 mg intravenous (iv) doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0011] In another aspect, the invention relates to the treatment of GPP in a patient by administering one 900 mg intravenous dose of an anti-IL-36R antibody to the patient, and if symptoms of GPP persist, an additional 900 mg intravenous dose of an anti-IL-36R antibody is administered one week after the first dose.

[0012] In one aspect, the present invention relates to a method of treating a generalized pustular psoriasis (GPP) flare in a patient, the method comprising administering to the patient two 900 mg intravenous (iv) doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0013] In one embodiment, the present invention relates to a method of treating GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0014] In one aspect, the present invention relates to a method of reducing or alleviating signs and symptoms of an acute flare-up of GPP in a patient; the method comprises administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0015] In one aspect, the present invention relates to a method of reducing the severity and duration of GPP symptoms, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0016] In one embodiment, the present invention relates to a method of treating a skin disorder associated with GPP, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0017] In one aspect, the invention relates to a method of preventing recurrence of GPP flare in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0018] In one aspect, the present invention relates to a method of reducing pain by at least 10% in a patient with GPP, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0019] In one aspect, the present invention relates to a method of improving quality of life by at least 10% in a patient with moderate to severe GPP symptoms, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0020] In one embodiment of any of the above aspects, the patient has a Physician's Global Assessment (GPPGA) total score for GPP of 2 or greater.

[0021] In one embodiment of any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater.

[0022] In one embodiment of any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater prior to administration of the first intravenous dose.

[0023] In one embodiment of any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater after administration of the first intravenous dose.

[0024] In one embodiment of any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater before and after administration of the first intravenous dose.

[0025] In one embodiment of any of the above aspects, the second dose is administered one week but less than two weeks after the first dose.

[0026] In one embodiment, the invention relates to a method of treating a GPP patient with a GPPGA Pustular subscore of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA Pustular subscore and, if the patient's GPPGA Pustular subscore of 2 or greater persists one week after the first dose, then administering a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0027] In one embodiment, the invention relates to a method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA total score and, if the patient's GPPGA total score of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0028] In one aspect, the invention relates to a method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustular subscore of 2 or greater, comprising the steps of: (a) administering an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody to the patient; (b) assessing the patient's GPPGA score and, if the patient's GPPGA total score of 2 or greater and GPPGA pustular subscore of 2 or greater persists one week after the initial dose, then administering a second 900 mg (iv) dose of spesolimab to the patient less than two weeks after the initial dose.

[0029] In one embodiment of any of the above aspects or embodiments, an optional third 900 mg intravenous dose of anti-IL-36R antibody is administered 2 weeks to 12 weeks after the second intravenous dose.

[0030] In one embodiment of any of the above aspects or embodiments, administration of two doses achieves one or more of the following results: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) Pustule subscore of 0 one week after administration of the second intravenous dose; and / or (b) GPPGA total score of 0 or 1 one week after administration of the second intravenous dose.

[0031] In one embodiment of any of the above aspects or embodiments, the results are maintained for up to and at least 12 weeks after administration of the second intravenous dose.

[0032] In one embodiment of any of the above aspects or embodiments, the method comprises administering to the patient a prophylactically effective amount of an anti-IL-36R antibody in one or more subcutaneous doses after the final intravenous dose has been administered.

[0033] In one embodiment of any of the above aspects or embodiments, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of said IL-36R antibody.

[0034] In one embodiment of any of the above aspects or embodiments, one, two, three or more subcutaneous doses are administered to the patient, the first subcutaneous dose being administered after the last intravenous dose.

[0035] In one embodiment of any of the above aspects or embodiments, the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

[0036] In one embodiment of any of the above aspects or embodiments, the patient remains in clinical remission as measured by a GPPGA total score of 0 or 1 for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose.

[0037] In one embodiment of any of the above aspects or embodiments, the anti-IL-36R antibody comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0038] In one embodiment of any of the above aspects or embodiments, the anti-IL-36R antibody comprises: Ia) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). II.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). III.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). IV.a) 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). Va) a light chain variable region comprising the amino acid sequence of SEQ ID NO:26 (L-CDR1); the amino acid sequence of SEQ ID NO:106 (L-CDR2); 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). VI.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); 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).

[0039] In one embodiment of any of the above aspects or embodiments, the anti-IL-36R antibody comprises: (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; or (ix) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101. Includes.

[0040] In one embodiment of any of the above aspects or embodiments, 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. Includes.

[0041] In one embodiment of any of the above aspects or embodiments, the anti-IL-36R antibody is spesolimab.

[0042] Additional features and advantages of the invention will be set forth in the following specification, and in part will be obvious from the specification, or may be learned by practice of the subject technology. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0043] The accompanying drawings, which are included to provide a further understanding of the invention, and which are incorporated in and constitute a part of this specification, illustrate aspects of the subject technology and, together with the description, serve to explain the principles of the invention. [Brief description of the drawings]

[0044] [Figure 1] Figure 1 shows the consort flow diagram for the study described in Example 1. *Other exclusions include study completion, achievement of global recruitment goals, and patients who did not have a flare within the 6-month screening period. †Patients were blinded to randomization treatment but could be eligible for an open-label dose of spesolimab on day 8. ‡Patients who did not complete the 16-week retention period after their last spesolimab dose did not enter the open-label extension study. Patients who did not continue in the open-label extension study were followed for 16 weeks after their last dose of study drug, which was the most recent time point of study drug administered during the study (e.g., day 1, day 8 if open-label spesolimab was administered, or rescue with open-label spesolimab if administered). OL, open label; OLE, open-label extension; SoC, standard of care. [Diagram 2]Figure 2 shows the study design as described in Example 1. *Days 2-7: Escape treatment (standard of care) may be provided in case of disease worsening, defined as a worsening of clinical status or skin and / or systemic manifestations of GPP, as defined by the investigator. †From day 8 onwards until week 12: Only one rescue dose with open-label spesolimab is permitted if patients who previously achieved a clinical response (GPPGA 0 / 1) to initial treatment with either spesolimab or placebo on day 1, or escape medication or open-label spesolimab on day 8, experience a recurrence of GPP flare (increase in GPPGA score ≥2 points and pustular component of GPPGA ≥2). Subsequent flares will be treated with standard of care according to physician choice. ‡Patients who do not require rescue treatment with open-label spesolimab will be followed until week 12 (end of treatment) before entering the open-label extension study. Patients who receive rescue treatment with open-label spesolimab between weeks 2 and 6 will be followed until week 12 (end of treatment) before entering the open-label extension study. At week 12, end of treatment will be considered for these patients if they qualify for entry into the open-label extension study. Patients who do not qualify for entry into the open-label extension study will be followed for 16 weeks (end of treatment / weeks 16–28) after the last dose of study drug, which is the most recent time point of study drug administered during the study (e.g., day 1, day 8 if open-label spesolimab is administered, or time of rescue with open-label spesolimab, if administered). EoT, end of treatment; GPP, generalized pustular psoriasis; GPPGA, physician's global assessment for generalized pustular psoriasis; iv, intravenous; OL, open label; OLE, open-label extension; R, randomized; SD, single dose; SoC, standard of care. [Figure 3A]Figure 3 shows the primary and key secondary outcomes. Panel A shows the proportion of patients with a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) Pustule subscore of 0 (complete pustule clearance) 1 week after treatment with spesolimab or placebo. Panel B shows the proportion of patients with a global GPPGA score of 0 or 1 (clear or almost clear skin) 1 week after treatment with a single 900 mg intravenous dose of spesolimab or placebo. CI, confidence interval. [Figure 3B] Figure 3 shows the primary and key secondary outcomes. Panel A shows the proportion of patients with a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) Pustule subscore of 0 (complete pustule clearance) 1 week after treatment with spesolimab or placebo. Panel B shows the proportion of patients with a global GPPGA score of 0 or 1 (clear or almost clear skin) 1 week after treatment with a single 900 mg intravenous dose of spesolimab or placebo. CI, confidence interval. [Figure 4A] Figure 4 shows the GPPGA pustular subscore over time by randomized treatment on day 1. Panels A and B show the proportion of patients by Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustular subscore at week 1 (day 8) and over time after receiving a single intravenous dose of placebo (panel A) or 900 mg of spesolimab (panel B), respectively. The dotted line indicates the proportion of patients who achieved a GPPGA pustular subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point was classified separately (gray bars). [Figure 4B]Figure 4 shows the GPPGA pustular subscore over time by randomized treatment on day 1. Panels A and B show the proportion of patients by Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustular subscore at week 1 (day 8) and over time after receiving a single intravenous dose of placebo (panel A) or 900 mg of spesolimab (panel B), respectively. The dotted line indicates the proportion of patients who achieved a GPPGA pustular subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point was classified separately (gray bars). [Figure 5A] Figure 5 shows the GPPGA total score over time by randomized treatment on Day 1. Panels A and B show the proportion of patients by Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) total score at week 1 (Day 8) and over time after receiving a single intravenous dose of placebo (Panel A) or 900 mg of spesolimab (Panel B), respectively. The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on Day 8, or rescue medication with open-label spesolimab at each time point was classified separately (gray bars). [Figure 5B] Figure 5 shows the GPPGA total score over time by randomized treatment on Day 1. Panels A and B show the proportion of patients by Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) total score at week 1 (Day 8) and over time after receiving a single intravenous dose of placebo (Panel A) or 900 mg of spesolimab (Panel B), respectively. The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on Day 8, or rescue medication with open-label spesolimab at each time point was classified separately (gray bars). [Figure 6A]FIG. 6 shows the GPPGA pustule subscore over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. Patients with a GPPGA total score of 2 or more and a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustule subscore of 2 or more on day 8 were able to receive open-label spesolimab. GPPGA pustule subscores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted line indicates the proportion of patients who achieved a GPPGA pustule subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). [Figure 6B]FIG. 6 shows the GPPGA pustule subscore over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. Patients with a GPPGA total score of 2 or more and a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustule subscore of 2 or more on day 8 were able to receive open-label spesolimab. GPPGA pustule subscores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted line indicates the proportion of patients who achieved a GPPGA pustule subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). [Figure 6C]FIG. 6 shows the GPPGA pustule subscore over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. Patients with a GPPGA total score of 2 or more and a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustule subscore of 2 or more on day 8 were able to receive open-label spesolimab. GPPGA pustule subscores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted line indicates the proportion of patients who achieved a GPPGA pustule subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). [Figure 6D]FIG. 6 shows the GPPGA pustule subscore over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. Patients with a GPPGA total score of 2 or more and a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustule subscore of 2 or more on day 8 were able to receive open-label spesolimab. GPPGA pustule subscores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted line indicates the proportion of patients who achieved a GPPGA pustule subscore of 0. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). [Figure 7A]FIG. 7 shows the GPPGA total score over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. On day 8, patients with a GPPGA total score of 2 or more and a GPPGA pustule subscore of 2 or more could receive open-label spesolimab. GPPGA total scores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). GPP, generalized pustular psoriasis; GPPGA, physician global assessment for generalized pustular psoriasis. [Figure 7B]FIG. 7 shows the GPPGA total score over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. On day 8, patients with a GPPGA total score of 2 or more and a GPPGA pustule subscore of 2 or more could receive open-label spesolimab. GPPGA total scores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). GPP, generalized pustular psoriasis; GPPGA, physician global assessment for generalized pustular psoriasis. [Figure 7C]FIG. 7 shows the GPPGA total score over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. On day 8, patients with a GPPGA total score of 2 or more and a GPPGA pustule subscore of 2 or more could receive open-label spesolimab. GPPGA total scores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). GPP, generalized pustular psoriasis; GPPGA, physician global assessment for generalized pustular psoriasis. [Figure 7D]FIG. 7 shows the GPPGA total score over time by randomized treatment on day 1 and open-label spesolimab treatment on day 8. On day 8, patients with a GPPGA total score of 2 or more and a GPPGA pustule subscore of 2 or more could receive open-label spesolimab. GPPGA total scores from baseline are shown for: all patients randomized to spesolimab with or without an open-label spesolimab dose on day 8 (Panel A); patients randomized to spesolimab who did not receive an open-label spesolimab dose on day 8 (Panel B); patients randomized to spesolimab who received an open-label spesolimab dose on day 8 (Panel C); and placebo who received an open-label spesolimab dose on day 8 (Panel D). The dotted lines indicate the proportion of patients who achieved a GPPGA total score of 0 or 1. *For this analysis, any use of escape medication, or open-label spesolimab on day 8, or rescue medication with open-label spesolimab at each time point were categorized separately (grey bars). GPP, generalized pustular psoriasis; GPPGA, physician global assessment for generalized pustular psoriasis. [Figure 8A]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 8B]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 8C]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 8D]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 8E]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 8F]FIG. 8 shows treatment responses in patients who received up to two doses of spesolimab on day 1 and the optional dose in the spesolimab group on day 8. Panel A shows GPPASI results; Panel B shows GPPASI 75 results; Panel C shows visual analogue scale results for pain; Panel D shows DLQI results; Panel E shows neutrophils over time in patients with neutrophils above the upper limit of normal (7×109 cells / L or higher) at baseline; Panel F shows C-reactive protein over time in patients with levels above the upper limit of normal (10 mg / L or higher) at baseline. The data set includes cases observed in patients randomized to spesolimab who received up to two doses of spesolimab, including patients who received open-label spesolimab on day 8. Arrows indicate days of intravenous administration of spesolimab. For this analysis, any value after open-label spesolimab on day 8 will be used, but any value after the use of escape medication or rescue medication with spesolimab will not be used as the worst outcome and missing values ​​will not be imputed in the calculation of medians and quartiles.DLQI, Dermatology Quality of Life Index;GPPASI, Generalized Pustular Psoriasis Area and Severity Index;GPPASI 75, 75% or greater improvement in Generalized Pustular Psoriasis Psoriasis Area and Severity Index;IQR, interquartile range;PainVAS, visual analog scale for pain. [Figure 9A]FIG. 9 shows the change from baseline in GPPGA scores (including GPPGA pustule subscore and GPPGA total score) in three patients after receiving the first and second doses of spesolimab on days 1 and 8, respectively. Panel A shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1250001012 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel B shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1276007001 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel C shows the change in GPPGA score (as well as skin erythema, scaling / escharging) in patient 1458001002 after receiving a first 900 mg intravenous (iv) dose of spesolimab and a second 900 mg intravenous dose of spesolimab one week later. [Figure 9B] FIG. 9 shows the change from baseline in GPPGA scores (including GPPGA pustule subscore and GPPGA total score) in three patients after receiving the first and second doses of spesolimab on days 1 and 8, respectively. Panel A shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1250001012 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel B shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1276007001 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel C shows the change in GPPGA score (as well as skin erythema, scaling / escharging) in patient 1458001002 after receiving a first 900 mg intravenous (iv) dose of spesolimab and a second 900 mg intravenous dose of spesolimab one week later. [Figure 9C]FIG. 9 shows the change from baseline in GPPGA scores (including GPPGA pustule subscore and GPPGA total score) in three patients after receiving the first and second doses of spesolimab on days 1 and 8, respectively. Panel A shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1250001012 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel B shows the change in GPPGA score (as well as skin erythema, scaling / scabbing) in patient 1276007001 after receiving the first 900 mg intravenous (iv) dose of spesolimab and the second 900 mg intravenous dose of spesolimab one week later. Panel C shows the change in GPPGA score (as well as skin erythema, scaling / escharging) in patient 1458001002 after receiving a first 900 mg intravenous (iv) dose of spesolimab and a second 900 mg intravenous dose of spesolimab one week later. [Figure 10] Figure 10 shows the PRO surveys for PSS, Pain VAS, FACIT-Fatigue, and DLQI scores. Higher total scores indicate greater disability or severity of intensity, except for FACIT-Fatigue, where higher scores indicate less fatigue. DLQI, Dermatology Quality of Life Index; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; PRO, Patient-Reported Outcomes; PSS, Psoriasis Symptom Scale; VAS, Visual Analog Scale. [Figure 11A]FIG. 11 shows absolute change from baseline in PRO scores over time. Panel A shows change from baseline in pain VAS score, Panel B shows change from baseline in PSS score, Panel C shows change from baseline in FACIT-Fatigue score, and Panel D shows change from baseline in DLQI score. Efficacy results for all randomized patients using an intention-to-treat analysis showed that all four PROs continued to improve over time; however, statistical significance versus placebo was not observed during week 1. The placebo curve begins to converge with the spesolimab curve after administration of open-label spesolimab on day 8. CI, confidence interval; DLQI, Dermatology Quality of Life Index; FACIT-Fatigue, Functional Assessment of Chronic Disease Therapy-Fatigue; IV, intravenous; OL, open label; PRO: patient-reported outcome; PSS Psoriasis Symptom Scale; VAS, visual analog scale. [Figure 11B] FIG. 11 shows absolute change from baseline in PRO scores over time. Panel A shows change from baseline in pain VAS score, Panel B shows change from baseline in PSS score, Panel C shows change from baseline in FACIT-Fatigue score, and Panel D shows change from baseline in DLQI score. Efficacy results for all randomized patients using an intention-to-treat analysis showed that all four PROs continued to improve over time; however, statistical significance versus placebo was not observed during week 1. The placebo curve begins to converge with the spesolimab curve after administration of open-label spesolimab on day 8. CI, confidence interval; DLQI, Dermatology Quality of Life Index; FACIT-Fatigue, Functional Assessment of Chronic Disease Therapy-Fatigue; IV, intravenous; OL, open label; PRO: patient-reported outcome; PSS Psoriasis Symptom Scale; VAS, visual analog scale. [Figure 11C]FIG. 11 shows absolute change from baseline in PRO scores over time. Panel A shows change from baseline in pain VAS score, Panel B shows change from baseline in PSS score, Panel C shows change from baseline in FACIT-Fatigue score, and Panel D shows change from baseline in DLQI score. Efficacy results for all randomized patients using an intention-to-treat analysis showed that all four PROs continued to improve over time; however, statistical significance versus placebo was not observed during week 1. The placebo curve begins to converge with the spesolimab curve after administration of open-label spesolimab on day 8. CI, confidence interval; DLQI, Dermatology Quality of Life Index; FACIT-Fatigue, Functional Assessment of Chronic Disease Therapy-Fatigue; IV, intravenous; OL, open label; PRO: patient-reported outcome; PSS Psoriasis Symptom Scale; VAS, visual analog scale. [Figure 11D] FIG. 11 shows absolute change from baseline in PRO scores over time. Panel A shows change from baseline in pain VAS score, Panel B shows change from baseline in PSS score, Panel C shows change from baseline in FACIT-Fatigue score, and Panel D shows change from baseline in DLQI score. Efficacy results for all randomized patients using an intention-to-treat analysis showed that all four PROs continued to improve over time; however, statistical significance versus placebo was not observed during week 1. The placebo curve begins to converge with the spesolimab curve after administration of open-label spesolimab on day 8. CI, confidence interval; DLQI, Dermatology Quality of Life Index; FACIT-Fatigue, Functional Assessment of Chronic Disease Therapy-Fatigue; IV, intravenous; OL, open label; PRO: patient-reported outcome; PSS Psoriasis Symptom Scale; VAS, visual analog scale. [Figure 12] FIG. 12 shows the distribution of maximum anti-drug antibody titers in female and male GPP patients after intravenous administration of spesolimab.

[0045] Detailed Description of the Invention In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the subject technology may be practiced without the use of some of these specific details. In other instances, well-known structures and techniques are not shown in detail in order to make the present invention easier to understand.

[0046] A phrase such as "one embodiment" does not mean that such an embodiment is essential to the invention or that such an embodiment applies to all configurations of the subject technology. A disclosure of one embodiment may apply to all configurations, or one or more configurations. An embodiment may provide one or more examples of the disclosure. A phrase such as "one embodiment" may refer to one or more embodiments, and vice versa. A phrase such as "one embodiment" does not mean that such an embodiment is essential to the subject technology or that such an embodiment applies to all configurations of the subject technology. A disclosure of one embodiment may apply to all embodiments, or one or more embodiments. An embodiment may provide one or more examples of the disclosure.

[0047] The inventors have surprisingly discovered, inter alia, that inhibition of the interleukin-36 pathway with a single dose of a humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the invention resulted in rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis, and no recurrence of GPP flares was observed 20 weeks after administration of a single dose.

[0048] Therefore, the present invention relates to compositions and methods for the treatment and / or prevention of GPP and its signs and symptoms. More specifically, the present invention relates to compositions and methods for the treatment and / or prevention of moderate to severe GPP, acute GPP, chronic GPP, and / or GPP flare in a mammal using an anti-IL-36R antibody or antigen-binding fragment thereof of the present invention. The compositions and methods comprise administering a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof to a mammal, wherein the anti-IL-36R antibody is administered in a single intravenous dose. In one embodiment, the anti-IL-36R antibody is administered in one or more intravenous doses, optionally followed by one or more subcutaneous doses.

[0049] Without wishing to be bound by this theory, it is believed that the anti-IL-36R antibody or antigen-binding fragment thereof binds to human anti-IL-36R and thus interferes with the binding of IL-36 agonists, thereby at least partially blocking the signaling cascade from IL-36R to inflammatory mediators. The anti-IL-36R antibody of the present invention is disclosed in U.S. Pat. No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0050] Acute GPP flares of various severity occur in most patients and may be idiopathic or triggered by external stimuli such as infection, use or withdrawal of corticosteroids, stress, or pregnancy. Moderate or severe GPP flares cause significant morbidity and mortality due to tender, painful skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia, and acute phase response, and sepsis. The acute phase is associated with a mean hospital stay of 10 days (range 3-44 days). The reported observed mortality rate of 7% in a retrospective study including 102 GPP cases seen in a tertiary care hospital in Johor, Malaysia may be an underestimate as not all GPP patients were included in the study. Mortality may also be underestimated due to not identifying the cause of death from GPP, which is mainly driven by infectious complications and extradermal organ manifestations such as renal, hepatic, respiratory, and cardiac failure. After a treatment response or spontaneous cessation of a flare, it is estimated that up to 50% of patients may suffer from chronic GPP, characterized by persistent erythema and scaling, which may also include articular symptoms.

[0051] Based on the above limitations, current therapeutic options are not suitable for long-term treatment and do not provide sustained responses in the majority of patients. Therefore, there is a great need to (i) develop highly effective treatments with rapid onset of action for patients presenting with acute GPP flares, and (ii) develop effective treatments for chronic GPP that reliably prevent the occurrence of flares and are safe and tolerable for lifelong treatment.

[0052] Classical symptoms of GPP flare as described by von Zumbusch are strongly correlated with polymorphisms in the IL-36R signaling pathway. Individuals with loss-of-function mutations in the IL36RN gene, which encodes an endogenous IL36R antagonist (IL-36RN), have a dramatically higher incidence of GPP, suggesting that uncontrolled upregulation of IL36 signaling due to abnormal IL36RN antagonism leads to the development of inflammation observed in GPP. Genetic human studies have demonstrated the occurrence of GPP clusters in families with loss-of-function mutations in IL36RN, leading to uncontrolled IL36R signaling. Mutations in other genes linked to the IL36 pathway, such as CARD14, also lead to GPP. Recently published gene expression studies have shown sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1 / IL-36 inflammatory axis is a potent inducer of disease pathology in GPP. Furthermore, a recent meta-analysis examined 233 published GPP cases. They found that 49 of 233 (21.0%) cases had recessive IL36RN alleles. These 49 recessive IL36RN alleles defined a GPP phenotype characterized by early onset and high risk of systemic inflammation.

[0053] IL36R is a cell surface receptor involved in inflammatory responses in the skin and intestine. It is a novel member of the IL1R family that forms a heterodimeric complex with IL1R accessory proteins. The heterodimeric IL36R system, which includes stimulatory (IL36α, IL36β, IL36γ) and inhibitory ligands (IL36Ra), shares many structural and functional similarities with other members of the IL1 / IL1R family, such as IL1, IL18, and IL33 (R17-3602). All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through unique cognate receptor proteins and, upon ligand binding, recruit a common IL1RacP subunit, activating NFκB and MAP kinase pathways in receptor-positive cell types. In human skin tissues, 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 (macrophage inflammatory protein)-1β, TNF-α, IL12, IL17, IL23, TGF (tumor growth factor)-β) and regulates the expression of tissue remodeling genes (e.g., matrix metalloproteinases, TGF-β). The link between GPP and IL36RN mutations is therefore somewhat similar to the well-established neonatal-onset aseptic multifocal osteomyelitis, periostitis, and pustulosis caused by the absence of interleukin-1 receptor antagonists. In this case, the absence of receptor antagonists allows the opposing action of interleukin-1, resulting in life-threatening systemic inflammation with concomitant skin and bone. These clinical features responded to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

[0054] I. Definition The term "about" generally refers to an acceptable degree of error or variation for the quantity measured, given the nature or accuracy of the measurement. Typical and exemplary degrees of error or variation are within 5% or within 3% or within 1% of a given value or set of values. For example, the expression "about 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all values ​​therebetween (e.g., 95.1, 95.2, etc. for the range of 95-105; or 97.1, 97.2, etc. for the range of 97-103; 99.1, 99.2, etc. for the range of 99-101). Numerical quantities given herein are approximate unless otherwise specified, meaning that the term "about" can be inferred when not specified.

[0055] "Pharmaceutical composition" in this context refers to a liquid or powder formulation in such a form that allows the biological activity of the active ingredient(s) to be demonstrably effective and does not contain any additional ingredients that are significantly toxic to the subject to whom it will be administered. Such compositions are sterile. "Powder" refers to a freeze-dried or lyophilized or spray-dried pharmaceutical composition for parenteral use. Powders are typically reconstituted or dissolved in water. Freeze-drying is a low-temperature dehydration process that involves freezing the product, applying a vacuum, and then removing the ice by sublimation. Freeze-drying results in a high-quality product due to the low temperatures used in processing. In a well-developed freeze-dried formulation, the shape and appearance of the product are maintained over time, and the quality of the rehydrated product is excellent. Spray-drying is another method of producing dry powders from liquids or slurries by using hot gas to rapidly dry with the goal of achieving a consistent particle size distribution.

[0056] As used herein, the terms "intravenous dose" and "subcutaneous dose" refer to the temporal administration sequence of anti-IL-36R antibody in addition to their usual meaning. Thus, an "intravenous dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); it may also be referred to as an "initial dose" or an "induction dose". A "subcutaneous dose" is a dose administered after an intravenous dose, which may also be referred to as a "subsequent dose" or a "maintenance dose". Intravenous and subcutaneous doses may all contain the same amount of anti-IL-36R antibody or antigen-binding fragment thereof, but may generally differ from each other in terms of the amount of antibody administered or the frequency of administration. In one embodiment, the intravenous dose is equal to or greater than the subcutaneous dose. An "intravenous dose" may also be interchangeably referred to as an "initial dose" or an "induction dose", which may be a single dose or alternatively a set of doses. A subcutaneous dose may also be referred to as a "subsequent dose" or a "maintenance dose", which may be a single dose or alternatively a set of doses for administration.

[0057] In certain embodiments, the amount of anti-IL-36R antibody contained in the induction / initial / intravenous and maintenance / subsequent / subcutaneous doses differs from each other during the course of treatment. In certain embodiments, one or more of the induction / intravenous doses each contain a first amount of the antibody or antigen-binding fragment thereof, and one or more of the maintenance / subsequent / subcutaneous doses each contain a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the amount of the antibody or antigen-binding fragment thereof in the second or subsequent amount. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5 or more) initial doses are administered as a "loading dose" or "leading dose" at the beginning of the treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the intravenous dose, induction dose, or initial dose is about 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg of anti-IL-36R antibody. In one embodiment, the subcutaneous dose, maintenance dose, or subsequent dose is about 150 mg, 225 mg, or 300 mg. In another embodiment, the subcutaneous dose or maintenance dose or subsequent dose is administered at least 2 weeks after the intravenous dose, induction dose, or initial dose.

[0058] The terms "antibody," "anti-IL-36R antibody," "humanized anti-IL-36R antibody," "humanized anti-IL-36R epitope antibody," and "mutated humanized anti-IL-36R epitope antibody" specifically encompass monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibodies with minor modifications, such as N-terminal and / or C-terminal truncations, and antibody fragments, e.g., variable domains, and other portions of antibodies that exhibit the desired biological activity, e.g., binding to IL-36R.

[0059] The term "monoclonal antibody" (mAb) refers to an antibody that is highly specific and directed against a single antigenic determinant or "epitope." Thus, the modifier "monoclonal" indicates an antibody that is directed against the same epitope and is not considered to require production of the antibody by any particular method. It should be understood that monoclonal antibodies may be made by any technique or method known in the art, including, for example, the hybridoma method (Kohler et al., 1975, Nature 256:495) or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567), or isolation of recombinantly produced monoclonal antibodies using phage antibody libraries using the techniques described in Clackson et al., 1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222: 581-597.

[0060] The term "monomeric" refers to a homogeneous antibody, e.g., for a full-length antibody, monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

[0061] A chimeric antibody consists of the variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, e.g., a mouse) and the constant regions of the heavy and light chains of an antibody from another species (e.g., a human), and can be obtained by linking a DNA sequence encoding the variable region of an antibody from a first species (e.g., a mouse) to a DNA sequence of the constant region of an antibody from a second species (e.g., a human) and transforming a host with an expression vector containing the linked sequences to enable it to produce the chimeric antibody. Alternatively, a chimeric antibody can also be an antibody in which one or more regions or domains of the heavy and / or light chains are identical to, homologous to, or variants of corresponding sequences in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. Chimeric antibodies can include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of the parent antibody, e.g., binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0062] The term "intravenous infusion" refers to the introduction of a drug into a vein of an animal or human patient over a period of more than about 15 minutes, typically about 30 to 90 minutes.

[0063] The term "intravenous bolus" or "intravenous push" refers to administration of a drug into a vein of an animal or human such that the organism receives the drug within about 15 minutes, typically within 5 minutes.

[0064] The term "subcutaneous administration" refers to the introduction of an agent by relatively slow and sustained delivery from a drug reservoir under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue. The pocket can be created by pinching the skin and lifting it away from the underlying tissue.

[0065] As used herein, the terms "treatment" and "therapy" and the like are meant to include therapeutic measures and preventive or suppressive measures for a disease or disorder that produce any clinically desirable or beneficial effect, including, but not limited to, alleviating or alleviating one or more symptoms, reversing, slowing, or stopping the progression of a disease or disorder. Thus, for example, the term treatment includes administration of an agent before or after the onset of a disease or disorder symptom, thereby preventing or eliminating one or more signs of a disease or disorder. As another example, the term includes combating a disease symptom by administering an agent after the clinical signs of a disease. Furthermore, administration of an agent after onset and after the occurrence of clinical symptoms (where administration affects a clinical parameter of a disease or disorder, such as the amount or extent of tissue damage or metastasis, regardless of whether the treatment results in remission of the disease) includes "treatment" or "therapy" as used herein. Furthermore, so long as a composition of the invention, alone or in combination with another therapeutic agent, reduces or ameliorates at least one symptom of the disorder being treated, compared to that symptom in the absence of the humanized anti-IL-36R antibody composition, the result should be deemed to be an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated.

[0066] The term "prophylactically effective amount" is used to refer to an amount effective at a dosage and for a period of time necessary to achieve a desired prophylactic result. Typically, a prophylactic dose is used in a subject prior to the onset of a GPP flare and / or prior to the onset of symptoms of GPP to prevent or inhibit the occurrence of an acute flare. In one embodiment, a subcutaneous dose as contemplated herein is a prophylactic dose used in an acute GPP patient after an intravenous dose to prevent the possible recurrence of a GPP flare in the patient.

[0067] II. Antibodies The anti-IL-36R antibodies of the present invention are disclosed in U.S. Pat. No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0068] 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 invention. Also described are binding agents comprising antigen-binding fragments of anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies.

[0069] Mechanism of action The anti-IL-36R antibody of the present invention is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R signaling. The binding of the anti-IL-36R antibody of the present invention to IL36R is expected to prevent the subsequent activation of IL36R by its cognate ligands (IL36α, β and γ) and downstream activation of proinflammatory and profibrotic pathways, with the aim of reducing inflammation mediated by epithelial cells / fibroblasts / immune cells and interrupting the inflammatory response that drives pathological cytokine production in generalized pustular psoriasis (GPP). As provided herein, the anti-IL-36R antibody of the present invention has been tested and found to be effective in treating patients with acute generalized pustular psoriasis (GPP), a severe inflammatory skin disease driven by unregulated IL36R activity.

[0070] IL-36R is also known as IL-1RL2 and IL-1Rrp2. Agonistic IL-36 ligands (α, β, or γ) are reported to bind to the IL-36 receptor and subsequently initiate a signaling cascade by forming a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) inhibit the signaling cascade.

[0071] The variable regions and CDRs of representative antibodies of the invention are disclosed below.

[0072] Anti-IL-36R mouse antibody sequence The variable regions and CDRs of a representative murine lead antibody (murine lead) of the invention are shown below.

[0073]

Table 1

[0074]

Table 2

[0075]

Table 3

[0076]

Table 4

[0077]

Table 5

[0078]

Table 6

[0079]

Table 7

[0080]

Table 8

[0081]

Table 9

[0082] Anti-IL-36R humanized antibody sequence Human framework sequences were selected for the mouse lead based on framework homology, CDR structure, conserved classical residues, conserved interface packing residues, and other parameters for generating humanized variable regions (see Example 5).

[0083] Representative humanized variable regions derived from antibodies 81B4 and 73C5 are shown below.

[0084] [Table 10] TIFF0007662804000015.tif72169

[0085] [Table 11] TIFF0007662804000017.tif217169

[0086] The CDR sequences from the humanized variable regions from antibodies 81B4 and 73C5 are shown below.

[0087] [Table 12]

[0088] [Table 13]

[0089] [Table 14]

[0090] [Table 15]

[0091] [Table 16]

[0092] [Table 17]

[0093] In one embodiment, the variable regions of the present invention are linked to a constant region, for example, the variable regions of the present invention are linked to the constant regions shown below to form the heavy or light chain of an antibody.

[0094] [Table 18]

[0095] Representative light and heavy chain sequences of the invention are shown below (humanized variable regions derived from antibodies 81B4 and 73C5 linked to constant regions).

[0096] [Table 19] TIFF0007662804000026.tif156169

[0097] [Table 20] TIFF0007662804000028.tif224169 TIFF0007662804000029.tif226169 TIFF0007662804000030.tif186169

[0098] The CDRs listed above are defined using the Chothia numbering system (Al-Lazikani et al., (1997) JMB 273, 927-948).

[0099] In one embodiment, an antibody of the invention comprises three light chain CDRs and three heavy chain CDRs, eg, as set out above.

[0100] In one embodiment, an antibody of the invention comprises a light chain and a heavy chain variable region as shown above. In one embodiment, a light chain variable region of the invention is fused to a light chain constant region, such as a kappa or lambda constant region. In one embodiment, a heavy chain variable region of the invention is fused to a heavy chain constant region, such as IgA, IgD, IgE, IgG or IgM, in particular IgG1, IgG2, IgG3 or IgG4.

[0101] The present invention provides an anti-IL-36R antibody (Antibody B1), comprising 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.

[0102] The present invention provides an anti-IL-36R antibody (antibody B2) comprising 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.

[0103] The present invention provides an anti-IL-36R antibody (antibody B3) comprising 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.

[0104] The present invention provides an anti-IL-36R antibody (antibody B4) comprising 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.

[0105] The present invention provides an anti-IL-36R antibody (antibody B5) comprising 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.

[0106] The present invention provides an anti-IL-36R antibody (antibody B6) comprising 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.

[0107] The present invention provides an anti-IL-36R antibody (antibody C3) comprising 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.

[0108] The present invention provides an anti-IL-36R antibody (Antibody C2) comprising 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.

[0109] The present invention provides an anti-IL-36R antibody (antibody C1), comprising 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.

[0110] Representative antibodies of the present invention are shown below.

[0111] [Table 21] TIFF0007662804000032.tif223169 TIFF0007662804000033.tif146169

[0112] [Table 22] TIFF0007662804000035.tif95169

[0113] In some embodiments, the humanized antibody exhibits blocking activity, whereby it reduces the binding of IL-36 ligand to the IL-36 receptor by at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. The ability of an antibody to block the binding of IL-36 ligand to the IL-36 receptor can be measured using competitive binding assays known in the art. Alternatively, the blocking activity of an antibody can be measured by assessing the biological effects of IL-36, such as the production of IL-8, IL-6, and GM-CSF (granulocyte macrophage colony stimulating factor), to determine whether signal transduction mediated by the IL-36 receptor is inhibited.

[0114] In a further aspect, the present invention provides a humanized anti-IL-36R antibody having favorable biophysical properties. In one aspect, the humanized anti-IL-36R antibody of the present invention is present in a buffer solution in at least 90% monomeric form, or at least 92% monomeric form, or at least 95% monomeric form. In a further aspect, the humanized anti-IL-36R antibody of the present invention remains in a buffer solution in at least 90% monomeric form, or at least 92% monomeric form, or at least 95% monomeric form for one month or four months.

[0115] In one embodiment, the humanized antibody of the invention is antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2 or antibody C3. Thus, in one embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 125 (antibody B1). In another embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 126 (antibody B2). In another embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 127 (antibody B3). In another embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 125 (antibody B4). In another embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 126 (antibody B5). In another embodiment, a humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 127 (antibody B6). In another embodiment, a humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 124 and the heavy chain sequence of SEQ ID NO: 138 (antibody C1). In another embodiment, a humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 139 (antibody C2). In another embodiment, a humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (antibody C3).

[0116] In a further embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 125 (antibody B1). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 126 (antibody B2). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 127 (antibody B3). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 125 (antibody B4). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 126 (antibody B5). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 118 and the heavy chain sequence of SEQ ID NO: 127 (antibody B6). In another embodiment, the humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 124 and the heavy chain sequence of SEQ ID NO: 138 (antibody C1). In another embodiment, a humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 139 (antibody C2). In another embodiment, a humanized antibody of the invention consists of the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (antibody C3).

[0117] In some embodiments, a humanized anti-IL-36R antibody (including an antigen-binding fragment thereof, such as the heavy and light chain variable regions) comprises the amino acid sequence of residues derived from Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2, or Antibody C3.

[0118] In a further embodiment, the present invention provides an anti-IL-36R antibody or antigen-binding fragment thereof that binds to human IL-36R in competition with an antibody of the present invention, such as antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3 described herein. The ability of an antibody or antigen-binding fragment to competitively bind to IL-36R can be measured using competitive binding assays known in the art.

[0119] Humanized anti-IL-36R antibodies optionally contain specific amino acid substitutions in the consensus or germline framework regions. Specific substitutions of amino acid residues at these framework positions can improve various aspects of antibody performance, including binding affinity and / or stability, over those demonstrated in humanized antibodies formed by "direct swapping" of CDRs or HVLs into human germline framework regions.

[0120] In some embodiments, the present invention describes other monoclonal antibodies having a light chain variable region having the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 10. In some embodiments, the present invention describes other monoclonal antibodies having a heavy chain variable region having the amino acid sequence set forth in any one of SEQ ID NOs: 11 to 20. Placing such CDRs in the FRs of the common variable domains of human heavy and light chains would result in a useful humanized antibody of the present invention.

[0121] In particular, the present invention provides monoclonal antibodies having the combination of light chain variable regions and heavy chain variable regions of SEQ ID NOs: 1 / 11, 2 / 12, 3 / 13, 4 / 14, 5 / 15, 6 / 16, 7 / 17, 8 / 18, 9 / 19, 10 / 20. Such variable regions may be combined with human constant regions.

[0122] In some embodiments, the present invention describes other humanized antibodies having a light chain variable region sequence having an amino acid sequence as set forth in any one of SEQ ID NOs: 76-86. In some embodiments, the present invention describes other humanized antibodies having a heavy chain variable region sequence having an amino acid sequence as set forth in any one of SEQ ID NOs: 87-101. In particular, the present invention provides monoclonal antibodies having a combination of light chain variable regions and heavy chain variable regions of SEQ ID NOs: 77 / 89, 80 / 88, 80 / 89, 77 / 87, 77 / 88, 80 / 87, 86 / 100, 85 / 101, 85 / 100. Such variable regions can be combined with human constant regions.

[0123] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising CDRs of SEQ ID NO: 77 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain amino acid sequence of SEQ ID NO: 77, and a humanized heavy chain variable domain comprising CDRs of SEQ ID NO: 89 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0124] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain amino acid sequence of SEQ ID NO: 80, and a humanized heavy chain variable domain comprising CDRs of SEQ ID NO: 88 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0125] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain amino acid sequence of SEQ ID NO: 80, and a humanized heavy chain variable domain comprising CDRs of SEQ ID NO: 89 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0126] In a further embodiment, the invention relates to an anti-IL-36R antibody, or antigen-binding fragment thereof, comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 77 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain amino acid sequence of SEQ ID NO: 77, and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO: 87 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0127] In a further embodiment, the invention relates to an anti-IL-36R antibody, or an antigen-binding fragment thereof, comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 77 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain amino acid sequence of SEQ ID NO: 77, and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO: 88 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0128] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain amino acid sequence of SEQ ID NO: 80, and a humanized heavy chain variable domain comprising CDRs of SEQ ID NO: 87 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0129] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 86 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain amino acid sequence of SEQ ID NO: 86, and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO: 100 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0130] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 85 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain amino acid sequence of SEQ ID NO: 85, and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO: 101 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 101. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0131] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 85 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain amino acid sequence of SEQ ID NO: 85, and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO: 100 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0132] In some specific embodiments, the humanized anti-IL-36R antibodies disclosed herein comprise at least one heavy or one light chain variable domain comprising the CDRs or HVLs of a murine monoclonal antibody or a humanized antibody as disclosed herein and the FRs of human germline heavy and light chain variable domains.

[0133] In a further aspect, the present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof comprising a light chain CDR1 (L-CDR1) sequence of any one of SEQ ID NOs: 21 to 29; a light chain CDR2 (L-CDR2) sequence of any one of SEQ ID NOs: 30 to 38; a light chain CDR3 (L-CDR3) sequence of any one of SEQ ID NOs: 39 to 47; a heavy chain CDR1 (H-CDR1) sequence of any one of SEQ ID NOs: 48 to 56; a heavy chain CDR2 (H-CDR2) sequence of any one of SEQ ID NOs: 57 to 66; and a heavy chain CDR3 (H-CDR3) sequence of any one of SEQ ID NOs: 67 to 75. In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the L-CDR1 listed above, the L-CDR2 listed above, and the L-CDR3 listed above, and a heavy chain variable region comprising the H-CDR1 listed above, the H-CDR2 listed above, and the H-CDR3 listed above.

[0134] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 21, 30, 39, 48, 57, and 67, respectively; or b) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 22, 31, 40, 49, 58, and 68, respectively; or c) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 23, 32, 41, 50, 59, and 69, respectively; or d) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 24, 33, 42, 51, 60, and 70, respectively; or e) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 25, 34, 43, 52, 61, and 71, respectively; or f) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 26, 35, 44, 53, 62, and 72, respectively; or g) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 27, 36, 45, 54, 63, and 73, respectively; or h) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 27, 36, 45, 54, 64, and 74, respectively; or i) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 27, 36, 45, 54, 64, and 73, respectively; or j) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 28, 37, 46, 55, 65, and 74, respectively; or k) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 29, 38, 47, 56, 66, and 75, respectively The present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising:

[0135] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 26, 103, 44, 53, 62, and 72, respectively; or b) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 26, 104, 44, 53, 62, and 72, respectively; or c) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 27, 36, 45, 107, 63, and 73, respectively; or d) the sequences of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 of SEQ ID NOs: 27, 36, 45, 107, 64, and 73, respectively; The present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising:

[0136] In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a combination of the L-CDR1, L-CDR2, and L-CDR3 listed above, and a heavy chain variable region comprising a combination of the H-CDR1, H-CDR2, and H-CDR3 listed above.

[0137] In specific embodiments, it is believed that chimeric antibodies having CDR regions exchanged between these exemplary immunoglobulins (i.e., replacing, for example, one or two CDRs from one of the mouse antibodies or humanized antibodies derived therefrom with similar CDRs from another mouse antibody or humanized antibody derived therefrom) may yield useful antibodies.

[0138] In certain embodiments, the humanized anti-IL-36R antibody is an antibody fragment. Various antibody fragments are generally discussed above, and there are techniques developed for the production of antibody fragments. Fragments can be derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al., 1985, Science 229:81). Alternatively, fragments can be produced directly in recombinant host cells. For example, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (see, e.g., Carter et al., 1992, Bio / Technology 10:163-167). According to another approach, F(ab')2 fragments can be directly isolated from recombinant host cell culture medium. Other techniques for the production of antibody fragments will be apparent to those skilled in the art. Thus, in one aspect, the invention provides antibody fragments comprising one of the CDRs described herein, in particular the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 combinations described herein. In a further aspect, the invention provides antibody fragments comprising the variable regions described herein, e.g. one of the light chain variable region and heavy chain variable region combinations described herein.

[0139] Certain embodiments include a F(ab')2 fragment of a humanized anti-IL-36R antibody comprising the light chain sequence of any of SEQ ID NOs: 115 or 118 in combination with the heavy chain sequence of SEQ ID NOs: 125, 126 or 127. Such embodiments may include an intact antibody comprising such a F(ab')2.

[0140] Certain embodiments include a F(ab')2 fragment of a humanized anti-IL-36R antibody comprising the light chain sequence of either SEQ ID NO: 123 or 124 in combination with the heavy chain sequence of SEQ ID NO: 138 or 139. Such embodiments may include an intact antibody comprising such a F(ab')2.

[0141] In some embodiments, the antibody or antibody fragment comprises a constant region that mediates effector functions. The constant region can provide an antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC) response against anti-IL-36R expressing target cells. The effector domain(s) can be, for example, the Fc region of an immunoglobulin molecule.

[0142] The effector domain of the antibody may be derived from any suitable vertebrate species and isotype. Isotypes derived from different animal species differ in their ability to mediate effector functions. For example, the ability of human immunoglobulins to mediate CDC and ADCC / ADCP is generally IgM≈IgG1≈IgG3>IgG2>IgG4 and IgG1≈IgG3>IgG2 / IgM / IgG4, respectively. Mouse immunoglobulins mediate CDC and ADCC / ADCP generally IgM≈IgG3>>IgG, respectively. 2b >IgG 2a >>IgG1 and IgG 2b >IgG 2a In another example, mouse IgG 2a mediates ADCC, whereas mouse IgG 2a Both IgM and IgM mediate CDC.

[0143] III. Drug Dosage and Administration The anti-IL-36R antibodies of the present invention are typically administered to patients as pharmaceutical compositions in which the antagonist is mixed with a pharma- ceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and the United States Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984). Pharmaceutical compositions may be formulated in any manner suitable for the intended route of administration. Examples of pharmaceutical formulations include lyophilized powders, slurries, aqueous solutions, suspensions, and sustained release formulations (see, e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al.(eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds. ) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipients, Marcel Dekker, NY; (See, Toxicity and Safety, Marcel Dekker, Inc., New York, NY.) Suitable routes of administration include intravenous injection (including intraarterial injection) and subcutaneous injection.

[0144] Representative examples of doses and dosing regimens according to the present invention are disclosed in Table A. Although doses of 900 mg and 750 mg are exemplified, similar dosing regimens equally apply to doses of 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, and 800 mg.

[0145] [Table 23] TIFF0007662804000037.tif233169 TIFF0007662804000038.tif73169

[0146] In one embodiment, one, two, or three or more intravenous dose(s) are administered to a patient in the dosing regimen listed in Table A, where the first subcutaneous dose is administered 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

[0147] In one embodiment, the present invention relates to the treatment of GPP in a patient by administering to the patient two 900 mg intravenous (iv) doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0148] In another aspect, the invention relates to the treatment of GPP in a patient by administering a single 900 mg intravenous dose of an anti-IL-36R antibody to the patient, and if GPP symptoms persist, administering an additional 900 mg intravenous dose of an anti-IL-36R antibody one week after the first dose.

[0149] In one aspect, the present invention relates to a method of treating a generalized pustular psoriasis (GPP) flare in a patient, the method comprising administering to the patient two 900 mg intravenous (iv) doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0150] In one embodiment, the present invention relates to a method of treating GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0151] In one aspect, the present invention relates to a method of reducing or alleviating signs and symptoms of an acute flare-up of GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0152] In one aspect, the present invention relates to a method of reducing the severity and duration of GPP symptoms, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0153] In one embodiment, the present invention relates to a method of treating a skin disorder associated with GPP, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0154] In one aspect, the invention relates to a method of preventing recurrence of GPP flare in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0155] In one aspect, the present invention relates to a method of reducing pain by at least 10% in a patient with GPP, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0156] In one aspect, the present invention relates to a method of improving quality of life by at least 10% in a patient with moderate to severe GPP symptoms, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than two weeks after the first dose.

[0157] In one embodiment related to any of the above aspects, the patient has a GPP Physician Global Assessment (GPPGA) total score of 2 or greater.

[0158] In one embodiment related to any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater, and a GPPGA pustule subscore of 2 or greater.

[0159] In one embodiment related to any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater prior to administration of the first intravenous dose.

[0160] In one embodiment related to any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater after administration of the first intravenous dose.

[0161] In one embodiment related to any of the above aspects, the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustule subscore of 2 or greater before and after administration of the first intravenous dose.

[0162] In one embodiment related to any of the above aspects, the second dose is administered one week but less than two weeks after the first dose.

[0163] In one embodiment, the invention relates to a method of treating a GPP patient with a GPPGA pustular subscore of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA pustular subscore and, if the patient's GPPGA pustular subscore of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0164] In one embodiment, the invention relates to a method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA total score and, if the patient's GPPGA total score of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0165] In one aspect, the invention relates to a method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA pustular subscore of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA score, and if the patient's GPPGA total score of 2 or greater and GPPGA pustular subscore of 2 or greater persists one week after the initial dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the initial dose.

[0166] In one embodiment related to any of the above aspects or embodiments, an optional third 900 mg intravenous dose of anti-IL-36R antibody is administered 2 to 12 weeks after the second intravenous dose.

[0167] In one embodiment, related to any of the above aspects or embodiments, administration of two doses achieves one or more of the following results: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) Pustule subscore of 0 one week after administration of the second intravenous dose; and / or (b) GPPGA total score of 0 or 1 one week after administration of the second intravenous dose.

[0168] In one embodiment related to any of the above aspects or embodiments, the results are maintained for up to and at least 12 weeks after administration of the second intravenous dose.

[0169] In one embodiment related to any of the above aspects or embodiments, the method comprises administering a prophylactically effective amount of an anti-IL-36R antibody to the patient in one or more subcutaneous doses after the final intravenous dose has been administered.

[0170] In one embodiment related to any of the above aspects or embodiments, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of said IL-36R antibody.

[0171] In one embodiment related to any of the above aspects or embodiments, one, two, three or more subcutaneous doses are administered to the patient, the first subcutaneous dose being administered after the last intravenous dose.

[0172] In one embodiment related to any of the above aspects or embodiments, the first subcutaneous dose is administered 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

[0173] In one embodiment related to any of the above aspects or embodiments, the patient remains in clinical remission as measured by a GPPGA total score of 0 or 1 for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose.

[0174] In one embodiment related to any of the above aspects or embodiments, the mammal or patient has: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at week 1; (b) a GPPGA Pustule subscore of 0, indicating no visible pustules at week 1; (c) a Generalized Pustular Psoriasis Psoriasis Area and Severity Index (GPPASI)75 at week 4; (d) a change from baseline in visual analog scale (VAS) score for pain at week 4; (e) a Psoriasis Symptom Scale (PSS) score at week 4. (f) change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT) score at week 4; (g) a GPPGA of 0 or 1 at week 4; (h) a GPPGA pustule subscore of 0, indicating no visible pustules at week 4; (i) GPPASI50 at weeks 1 and 4; or (j) change from baseline in GPPASI pustule, erythema or scaling severity subscores at weeks 1 and 4. In a related embodiment, the proportion of patients responding to dosing is statistically significantly higher compared to placebo patients for any of the listed endpoints.

[0175] Pharmaceutical Compositions and Their Administration The antibody of the present invention may be administered either alone or in combination with other drugs. Examples of antibodies for use in such pharmaceutical compositions include antibodies or antibody fragments having a light chain variable region amino acid sequence of any of SEQ ID NOs: 1 to 10. Examples of antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having a heavy chain variable region amino acid sequence of any of SEQ ID NOs: 11 to 20.

[0176] Further examples of antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having a light chain variable region amino acid sequence of any of SEQ ID NOs: 76 to 86. Preferred antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having a heavy chain variable region amino acid sequence of any of SEQ ID NOs: 87 to 101.

[0177] Further examples of antibodies for use in such pharmaceutical compositions also include humanized antibodies or antibody fragments having the light chain variable regions and heavy chain variable regions of any of SEQ ID NOs:77 and 89, SEQ ID NOs:80 and 88, SEQ ID NOs:80 and 89, SEQ ID NOs:77 and 87, SEQ ID NOs:77 and 88, SEQ ID NOs:80 and 87, SEQ ID NOs:86 and 100, SEQ ID NOs:85 and 101, or SEQ ID NOs:85 and 10.

[0178] Further examples of antibodies for use in such pharmaceutical compositions also include humanized antibodies having the light chain region amino acid sequence of any of SEQ ID NOs: 115, 118, 123 or 124. Preferred antibodies for use in such pharmaceutical compositions also include humanized antibodies having the heavy chain variable region amino acid sequence of any of SEQ ID NOs: 125, 126, 127, 138 or 139.

[0179] Further examples of antibodies for use in such pharmaceutical compositions also include antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2 or antibody C3.

[0180] Various delivery systems are known and can be used to administer the IL-36R binding agent. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-36R binding agent can be administered, for example, by infusion, bolus, or injection, and can be administered together with other biologically active agents, for example, chemotherapeutic agents. Administration can be systemic or local. In a preferred embodiment, administration is by subcutaneous injection. Such a formulation for injection can be prepared, for example, in a pre-filled syringe, which can be administered once every two weeks.

[0181] In one aspect, the present invention provides a product comprising a subcutaneous administration device, which delivers a fixed dose of the antibody of the present invention to a patient.In some embodiments, the subcutaneous administration device is a pre-filled syringe, an autoinjector, or a large volume injection device.For example, the MyDose™ product from Roche, which is a disposable injection device that allows subcutaneous administration of large volumes of liquid drugs, can be used as the administration device.Many reusable pen and autoinjector delivery devices have application for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AutoPen™ (Owen Mumford, Woodstock, UK), Disentronic™ Pen (Disetronic Medical Systems, Burgdorf, Switzerland), Humalog Mix 75 / 25™ Pen, Humalog™ Pen, Humalin 70 / 30™ Pen (Eli Lilly & Co., Indianapolis, IN), Novopen™ I, II and III (Novo Nordisk, Copenhagen, Denmark), Novopen Jr.™ (Novo Nordisk, Copenhagen, Denmark), BD™ Pen (Becton Dickinson & Co., Franklin Lakes, NJ), OptiPen™, OptiPen Pro™, OptiPen Starlet™, and OptiClick™ (Sanofi Aventis, Frankfurt, Germany), to name a few. Examples of disposable pen delivery devices having application for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the Solostar™ pen (Sanofi-Aventis), FlexPen™ (Novo Nordisk), and KwikPen™ (Eli Lilly and Company), the SuperClick™ autoinjector (Amgen, Thousand Oaks, Calif.), Penlet™ (Haselmeyer, Stuttgart, Germany), EpiPen (Dey, LP), and Humira™ pen (Abbott Laboratories, Abbott Park III), YPSOMATE™, YPSOMATE2.25™, and VAIROJECT™ (Ipsmed, Burgdorf, Switzerland), to name a few.Additional information regarding exemplary delivery devices that can be used with the antibodies of the invention can be found, for example, in CH705992A2, WO2009 / 040602, WO2016 / 169748, WO2016 / 179713.

[0182] In specific embodiments, the IL-36R binding agent composition is administered by injection, using a catheter, using a suppository, or using an implant, which is a porous, non-porous, or gel-like material, such as a membrane, e.g., a silastic membrane, or a fabric. Typically, when administering the composition, a material is used that the anti-IL-36R antibody or agent does not absorb.

[0183] In other embodiments, the anti-IL-36R antibody or agent is delivered in a controlled release system. In one embodiment, a pump may be used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In other embodiments, polymeric materials may be used (see, e.g., Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). Other controlled release systems are discussed above, e.g., by Langer.

[0184] An anti-IL-36R binding agent (eg, an anti-IL-36R antibody) can be administered as a pharmaceutical composition comprising a therapeutically effective amount of the binding agent and one or more pharma- ceutically compatible ingredients.

[0185] In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is present in a pharmaceutical formulation (as described in co-pending PCT Publication No. 20200185479, published September 17, 2020, the entire contents of which are hereby incorporated by reference in their entirety) suitable for administration to a mammal or patient according to any one of the aspects described herein. Various examples of this embodiment are described below as numbered items (1, 2, 3, etc.) for convenience. These are provided as examples and do not limit the subject technology. It is noted that any of the subordinate items may be combined in any combination or placed in their own independent items, e.g., item 1. Other items may be presented in the same manner.

[0186] 1. A method of treating a generalized pustular psoriasis (GPP) flare in a patient, the method comprising administering to the patient two 900 mg intravenous (iv) doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0187] 2. A method of treating GPP in a patient by administering to the patient a single 900 mg intravenous dose of an anti-IL-36R antibody, and if GPP symptoms persist, administering an additional 900 mg intravenous dose of an anti-IL-36R antibody one week after the initial dose.

[0188] 3. A method of treating GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0189] 4. A method of reducing or alleviating signs and symptoms of an acute flare-up of GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0190] 5. A method of reducing the severity and duration of symptoms of GPP, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0191] 6. A method of treating a skin disorder associated with GPP, comprising administering to a patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0192] 7. A method of preventing recurrence of GPP flare in a patient, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0193] 8. A method of reducing pain by at least 10% in a patient with GPP, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0194] 9. A method of improving quality of life by at least 10% in a patient with moderate to severe GPP symptoms, the method comprising administering to the patient two 900 mg intravenous doses of an anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

[0195] 10. The method of any of items 1 to 9, wherein the patient has a GPP Physician Global Assessment (GPPGA) total score of 2 or greater.

[0196] 11. The method of any of items 1 to 10, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or more and a GPPGA Pustule subscore of 2 or more.

[0197] 12. The method of any of items 1 to 11, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater prior to administration of the first intravenous dose.

[0198] 13. The method of any of items 1 to 12, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater after administration of the first intravenous dose.

[0199] 14. The method of any of items 1 to 13, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater before and after administration of the first intravenous dose.

[0200] 15. The method of any of items 1-14, wherein the second dose is administered one week but less than two weeks after the first dose.

[0201] A method of treating a GPP patient with a GPPGA pustular subscore of 16.2 or greater, the method comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA pustular subscore and, if the patient's GPPGA pustular subscore of 2 or greater persists one week after the initial dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the initial dose.

[0202] A method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 17.2 or greater, the method comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA total score, and if the patient's GPPGA total score of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0203] A method of treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 18.2 or greater and a GPPGA pustular subscore of 2 or greater, comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv1) dose of an anti-IL-36R antibody; (b) assessing the patient's GPPGA score, and if the patient's GPPGA total score of 2 or greater and GPPGA pustular subscore of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0204] 19. The method of any of items 1-18, wherein an optional third 900 mg intravenous dose of anti-IL-36R antibody is administered 2-12 weeks after the second intravenous dose.

[0205] Administration of 20.2 doses resulted in the following: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) Pustule subscore of 0 one week after administration of the second intravenous dose; and / or (b) GPPGA total score of 0 or 1 one week after administration of the second intravenous dose 20. The method according to any one of items 1 to 19, which achieves one or more of the above.

[0206] 21. The method of item 20, wherein the results are maintained for up to and at least 12 weeks after administration of the second intravenous dose.

[0207] 22. The method according to any of items 1 to 21, wherein the method further comprises administering to the patient a prophylactically effective amount of an anti-IL-36R antibody in one or more subcutaneous doses after the final intravenous dose has been administered.

[0208] 23. The method of item 22, wherein each of the one or more subcutaneous doses contains 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody.

[0209] 24. The method of item 23, wherein one, two, three or more subcutaneous doses are administered to the patient, the first subcutaneous dose being administered after the last intravenous dose.

[0210] 25. The method of item 24, wherein the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

[0211] 26. The method of any of items 1-25, wherein the patient remains in clinical remission as measured by a GPPGA total score of 0 or 1 for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose.

[0212] 27. The method according to any of Items 1 to 26, wherein the anti-IL-36R antibody comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0213] 28. The method according to any one of items 1 to 27, wherein the anti-IL-36R antibody comprises: Ia) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). II.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). III.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3). IV.a) 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). Va) a light chain variable region comprising the amino acid sequence of SEQ ID NO:26 (L-CDR1); the amino acid sequence of SEQ ID NO:106 (L-CDR2); 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). VI.a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); 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).

[0214] 29. Anti-IL-36R antibody: (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. 29. The method according to any one of items 1 to 28, comprising:

[0215] 30. Anti-IL-36R antibody: 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. 30. The method according to any one of items 1 to 29, comprising:

[0216] 31. The method of any of items 1 to 30, wherein the anti-IL-36R antibody is spesolimab.

[0217] 32. A method of treating a generalized pustular psoriasis (GPP) flare in a patient, the method comprising administering to the patient two 900 mg intravenous (iv) doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0218] 33. A method of treating GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0219] 34. A method of reducing or alleviating signs and symptoms of an acute flare-up of GPP in a patient, the method comprising administering to the patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0220] 35. A method of reducing the severity and duration of symptoms of GPP, the method comprising administering to a patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0221] 36. A method of treating skin disorders associated with GPP, comprising administering to a patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0222] 37. A method of preventing recurrence of GPP flare in a patient, the method comprising administering to the patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0223] 38. A method of reducing pain by at least 10% in a patient with GPP, the method comprising administering to the patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0224] 39. A method of improving quality of life by at least 10% in a patient with moderate to severe GPP symptoms, the method comprising administering to the patient two 900 mg intravenous doses of spesolimab, wherein the second dose is administered less than two weeks after the first dose.

[0225] 40. The method of any of items 1 to 39, wherein the patient has a GPP Physician Global Assessment (GPPGA) total score of 2 or greater.

[0226] 41. The method of any of items 1 to 40, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or more and a GPPGA pustule subscore of 2 or more.

[0227] 42. The method of any of items 1 to 41, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater prior to administration of the first intravenous dose.

[0228] 43. The method of any of items 1 to 42, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater after administration of the first intravenous dose.

[0229] 44. The method of any of items 1 to 43, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater and a GPPGA Pustule subscore of 2 or greater before and after administration of the first intravenous dose.

[0230] 45. The method of any of items 1 to 44, wherein the second dose is administered one week but less than two weeks after the first dose.

[0231] A method of treating a GPP patient with a GPPGA pustular subscore of 46.2 or greater, the method comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of spesolimab; (b) assessing the patient's GPPGA pustular subscore and, if the patient's GPPGA pustular subscore of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0232] A method of treating a GPP patient having a GPP Physician's Global Assessment (GPPGA) total score of 47.2 or greater, the method comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv) dose of spesolimab; (b) assessing the patient's GPPGA total score and, if the patient's GPPGA total score of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0233] A method for treating a GPP patient with a Physician's Global Assessment of GPP (GPPGA) total score of 48.2 or greater and a GPPGA pustular subscore of 2 or greater, the method comprising the steps of: (a) administering to the patient an initial 900 mg intravenous (iv1) dose of spesolimab; (b) assessing the patient's GPPGA score and, if the patient's GPPGA total score of 2 or greater and GPPGA pustular subscore of 2 or greater persists one week after the first dose, then administering to the patient a second 900 mg (iv) dose of spesolimab less than two weeks after the first dose.

[0234] 49. The method of any of items 1-48, wherein an optional third 900 mg intravenous dose of spesolimab is administered 2 to 12 weeks after the second intravenous dose.

[0235] The 50.2 doses will be administered as follows: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) Pustule subscore of 0 one week after administration of the second intravenous dose; and / or (b) GPPGA total score of 0 or 1 one week after administration of the second intravenous dose 50. The method according to any one of items 1 to 49, which achieves one or more of the following results.

[0236] 51. The method of item 50, wherein the results are maintained for up to and at least 12 weeks after administration of the second intravenous dose.

[0237] 52. The method of any of items 1 to 51, further comprising administering to the patient a prophylactically effective amount of spesolimab in one or more subcutaneous doses after the final intravenous dose has been administered.

[0238] 53. The method of item 52, wherein each of the one or more subcutaneous doses contains 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of spesolimab.

[0239] 54. The method of item 53, wherein one, two, three or more subcutaneous doses are administered to the patient, the first subcutaneous dose being administered after the last intravenous dose.

[0240] 55. The method of item 54, wherein the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

[0241] 56. The method of any of items 1 to 55, wherein the patient remains in clinical remission as measured by a GPPGA total score of 0 or 1 for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose.

[0242] 57. The method of any of items 1 to 56, wherein the patient experiences an improvement in Psoriasis Symptom Scale (PSS) score within 1, 4, or 12 weeks after receiving a dose(s) of spesolimab; wherein the improvement is at least 10% when the PSS score after administration of the anti-IL-36R antibody or spesolimab is compared to the patient's baseline PSS score prior to administration.

[0243] 58. The method of any of items 1 to 57, wherein the patient experiences an improvement in Functional Assessment of Chronic Disease Therapy-Fatigue (FACIT-Fatigue) score within 1, 4, or 12 weeks after receiving a dose(s) of spesolimab; wherein the improvement is at least 10% when the FACIT-Fatigue score after administration of the anti-IL-36R antibody or spesolimab is compared to the patient's baseline FACIT-Fatigue score prior to administration.

[0244] 59. The method of any of items 1 to 58, wherein the patient experiences an improvement in Dermatology Quality of Life Index (DLQI), Psoriasis Symptom Scale (PSS), Visual Analog Scale (VAS), or Functional Assessment of Chronic Disease Therapy-Fatigue (FACIT-Fatigue) score within 1, 4, or 12 weeks after receiving a dose(s) of spesolimab; wherein the improvement is at least 10% when the DQLI, PSS, VAS, or FACIT-Fatigue score at 1, 4, or 12 weeks after administration of the anti-IL-36R antibody or spesolimab is compared to the patient's baseline DQLI, PSS, VAS, or FACIT-Fatigue score prior to administration.

[0245] 60. A method of improving Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), Visual Analog Scale (VAS), or Functional Assessment of Chronic Disease Therapy-Fatigue (FACIT-Fatigue) score in a patient with GPP, the method comprising administering to the patient one 900 mg intravenous (iv) dose of spesolimab and optionally a second 900 mg intravenous dose of spesolimab; wherein the second optional dose of spesolimab is administered less than 2 weeks after the first dose if the patient has persistent GPP symptoms (e.g., a GPPGA total score of 2 or greater and / or a GPPGA pustular subscore of 2 or greater).

[0246] 61. A method of improving Functional Assessment of Chronic Disease Therapy-Fatigue (FACIT-Fatigue) score in a patient with GPP, the method comprising administering to the patient one 900 mg intravenous (iv) dose of spesolimab and optionally a second 900 mg intravenous dose of spesolimab; wherein the second optional dose of spesolimab is administered less than 2 weeks after the first dose if the patient persists with GPP symptoms (e.g., a GPPGA total score of 2 or greater and / or a GPPGA pustular subscore of 2 or greater).

[0247] 62. A method of improving Dermatology Life Quality Index (DLQI) score in a patient with GPP, the method comprising administering to the patient one 900 mg intravenous (iv) dose of spesolimab and optionally a second 900 mg intravenous dose of spesolimab; wherein the second optional dose of spesolimab is administered less than 2 weeks after the first dose if the patient persists with GPP symptoms (e.g., a GPPGA total score of 2 or greater and / or a GPPGA pustule subscore of 2 or greater).

[0248] 63. The method of any of items 59 to 61, wherein the improvement is at least 10% when the score at 1, 4, or 12 weeks after administration of spesolimab is compared to the score at the patient's baseline before administration.

[0249] 64. The method according to any of items 1 to 63, wherein administration(s) of spesolimab results in lower maximum anti-drug antibody titers at weeks 2, 4, 6, 8, 10 and / or 12 of treatment.

[0250] Further, the pharmaceutical composition may be provided as a pharmaceutical kit comprising (a) a container containing an IL-36R binding agent (e.g., an anti-IL-36R antibody) in lyophilized form, and (b) a second container containing a pharma- ceutically acceptable diluent (e.g., sterile water) for injection. The pharma- ceutically acceptable diluent may be used for reconstitution or dilution of the lyophilized anti-IL-36R antibody or agent. Optionally, such container(s) may be accompanied by a notice in a format mandated by a governmental authority regulating the manufacture, use, or sale of pharmaceuticals or biological products, the notice reflecting approval by the authority for manufacture, use, or sale for administration to humans.

[0251] Administration of such combination therapy may have an additive or synergistic effect on disease parameters (eg, severity of symptoms, number of symptoms, or frequency of recurrences).

[0252] With regard to therapeutic regimens for combined administration, in a specific embodiment, the anti-IL-36R antibody or IL-36R binding agent is administered simultaneously with the therapeutic agent. In another specific embodiment, the therapeutic agent is administered at least 1 hour and up to several months before or after administration of the anti-IL-36R antibody or IL-36R binding agent, for example at least 1 hour, 5 hours, 12 hours, 1 day, 1 week, 1 month, or 3 months before or after administration of the anti-IL-36R antibody or IL-36R binding agent.

[0253] The present invention is further described in the following examples, which do not limit the scope of the invention.

[0254] Working Example Example 1: Trial of Spesolimab for Generalized Pustular Psoriasis summary Background: Generalized pustular psoriasis is a rare, life-threatening, inflammatory skin disease characterized by widespread eruptions of sterile pustules. Dysregulated interleukin-36 signaling is involved in its pathogenesis. We compared spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, to placebo in a phase 2 study in patients with flares of generalized pustular psoriasis.

[0255] METHODS: Patients with a flare of generalized pustular psoriasis were randomly assigned in a 2:1 ratio to receive a single 900 mg intravenous dose of spesolimab or placebo. The primary outcome was a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) pustule subscore of 0 (range 0-4, with 0 indicating no pustules and 4 indicating severe pustules) at week 1. The key secondary outcome was a GPPGA total score of 0 or 1 (clear or almost clear) at week 1 (range 0-4, with higher scores indicating greater disease severity).

[0256] RESULTS: A total of 85 patients were screened, and 53 were enrolled: 35 were assigned to receive spesolimab and 18 were assigned to receive placebo. Baseline GPPGA pustular subscores were 3 in 46% and 39% of patients in the spesolimab and placebo groups, respectively, and 4 in 37% and 33%. At the end of week 1, a pustular subscore of 0 was achieved in 19 of 35 (54%) patients receiving spesolimab versus 1 of 18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21.5 to 67.2; P<0.001). At the end of week 1, a GPPGA total score of 0 or 1 was achieved by 15 of 35 (43%) patients in the spesolimab group and 2 of 18 (11%) patients in the placebo group (difference, 32 percentage points; 95% confidence interval, 2.2 to 52.7); P = .024). Drug reactions with eosinophilia and systemic symptoms were reported in 2 spesolimab-treated patients. Infections occurred in 17% of patients treated with spesolimab during week 1. Antidrug antibodies were detected in 23 of 50 (46%) patients who received at least one dose of spesolimab.

[0257] Conclusions: In a 1-week phase 2 study in patients with flares of generalized pustular psoriasis, the IL-36 receptor inhibitor spesolimab resulted in a higher proportion of lesions clearing than placebo, but was accompanied by more infections and systemic drug reactions. Longer and larger studies are needed to determine the effects and risks of spesolimab in pustular psoriasis (funded by Boehringer Ingelheim; ClinicalTrials.gov Identifier: NCT03782792).

[0258] Introduction Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening, autoinflammatory skin disease characterized by widespread, sterile, visible pustular eruptions with or without systemic symptoms of pain, fever, general malaise, fatigue, and extracutaneous manifestations such as arthritis and neutrophilic cholangitis. The clinical course of GPP may relapse with recurrent flares or may persist with intermittent flares. Mortality ranges from 2% to 16% and is due to septic shock and cardiopulmonary failure. The frequency of flares varies from patient to patient, and flares may be spontaneous or triggered by upper respiratory tract infections, stress, medications, drug withdrawal, and pregnancy. The disease has a detrimental effect on quality of life.

[0259] There are no therapies approved for the disease in the United States or Europe, and management includes cyclosporine, retinoids, methotrexate, and biologics. Biologics that inhibit tumor necrosis factor alpha (adalimumab, infliximab, certolizumab pegol), interleukin (IL)-17 / IL-17 receptor (secukinumab, brodalumab, ixekizumab), and IL-23 (risankizumab, guselkumab) have been approved for use in Japan, Taiwan, and Thailand based on small trials and studies of these drugs in plaque psoriasis, as well as small randomized trials in the GPP.

[0260] The role of the IL-36 pathway in GPP is supported by the discovery of loss-of-function mutations in the IL-36 receptor antagonist gene (IL36RN) and related genes (CARD14, AP1S3, SERPINA3, MPO) and the overexpression of IL-36 cytokines in GPP skin lesions. Clinical improvement with spesolimab, a humanized anti-IL-36 receptor monoclonal antibody, was observed in seven patients with GPP flares in an open-label phase 1 study.

[0261] The inventors conducted a phase 2 randomized study to investigate the efficacy and safety of spesolimab versus placebo in patients with GPP flare. Because acute and severe flares of this disorder are life-threatening, one dose of drug was selected for the study design, with a one-week placebo-controlled period, and patients in both groups were offered the opportunity to receive open-label spesolimab on day 8. At the end of the study, week 12, patients were offered to enroll in another open-label extension study of spesolimab (ClinicalTrials.gov identification number: NCT03886246).

[0262] method Study design This phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted from February 20, 2019 to January 5, 2021 and enrolled patients from 37 sites in 12 countries. Patients presenting with GPP flare were randomly assigned in a 2:1 ratio to receive a single 900 mg intravenous dose of spesolimab or placebo (Figure 1). Randomization was performed using a two-way response system with stratification factors of Japanese vs. non-Japanese ethnicity. Patients and investigators were blinded to the treatment group allocation administered on Day 1 throughout the study until the database was locked for analysis. On day 8, patients in both groups were eligible to receive a single 900 mg intravenous dose of open-label spesolimab (which led to crossover from placebo to spesolimab in some patients) if they showed persistent symptoms based on predefined thresholds consisting of a Physician's Global Assessment of GPPs (GPPGA) total score of ≥2 (ranging from 0 [clear skin] to 4 [severe disease]) at the end of week 1 and a clinician assessment of GPP severity based on a modified PGA and GPPGA pustule subscore of ≥2 (ranging from 0 [no visible pustules] to 4 [severe pustules]) at week 1. The GPPGA total score is the average of the subscores [pustules, erythema, and scaling]; (see Supplementary Information below). After 1 week, rescue treatment with a single 900 mg intravenous dose of spesolimab could be administered in case of recurrence of flare (defined as an increase of ≥2 points in both GPPGA total score and pustule subscore after initially achieving a GPPGA total score of 0 or 1). Patients who achieved clinical improvement and completed the study without flare symptoms were eligible to enter a 5-year open-label extension study (ClinicalTrials.gov Identifier: NCT03886246). Escape treatment with standard of care, at the treating physician's choice, was permitted for patients who experienced disease worsening during the first week that required immediate treatment and for patients with disease worsening after 1 week who were not eligible for rescue medication with open-label spesolimab. The use of escape treatment in the first week was mandatory for patient safety, as GPP flares can be life-threatening.Any patient who received escape medication was deemed to have not achieved a response (non-response) in the analyses for the primary and key secondary endpoints at Week 1. Details of the study design are in the protocol below and Figure 2.

[0263] Patients aged 18-75 years were eligible for enrollment if they had a history of GPP consistent with diagnostic criteria according to the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria1. Analysis of the coding sequences of the three main GPP-associated genes (IL36RN, CARD14, AP1S3) was performed on DNA extracts from blood samples, and patients were enrolled regardless of IL36RN mutation status. Patients had to have a GPP flare of moderate to severe intensity (defined as a GPPGA total score of ≥3, new or worsening pustules, a GPPGA pustule subscore of ≥2, and ≥5% of body surface area with erythema and the presence of pustules). Important exclusion criteria included patients with plaque-type psoriasis without pustules or with pustules limited to the psoriatic plaques, acute generalized exanthematous pustulosis triggered by medication, immediately life-threatening GPP flares requiring intensive care treatment, and the need to currently be treated with methotrexate, cyclosporine, or retinoids, or any limited medication.

[0264] Evaluation items The primary outcome was achievement of a GPPGA pustule subscore of 0 (clear) at the end of week 1. The key secondary outcome was a GPPGA score of 0 or 1 (clear or almost clear) at the end of week 1. Secondary outcomes were primarily at week 4, when some patients could receive open-label spesolimab on day 8. Secondary outcomes at week 4 included: ≥75% improvement in the Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI75; GPPASI is an adaptation of the PASI score, in which induration is replaced by a pustular component; scores range from 0 [lowest severity] to 72 [highest severity]), change from baseline in the Visual Analog Pain Scale (VAS, range from 0 [no pain] to 100 [severe pain]), change from baseline in the Psoriasis Symptom Scale (PS S; patient-reported psoriasis pain, redness, itching, and burning; range 0 to 16, higher scores indicate more severe symptoms), and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue; patient-reported impact of fatigue on daily activities; range 0 to 52, lower scores indicate greater impact). There were two additional secondary endpoints assessed at weeks 1 and / or 4, as well as the protocol and statistical analysis plan, as listed below.

[0265] Details of the study outcomes, as well as a list of exploratory endpoints, are listed in Supplementary Table S3 below.

[0266] Safety events at week 1 (through the first 8 days of the study) and through week 12 included treatment-emergent and serious adverse events. Adverse events were assessed by investigators blinded to treatment assignment until after the database was locked for the final analysis of the study. During the course of the study, adverse events that occurred were collected, recorded in electronic case report forms, and reported by the investigators to the sponsor. The intensity of adverse events was assessed by the investigators and graded according to the RCTC version 2.0 developed by the Organization for Rheumatology Outcomes Measures (OMERACT).

[0267] Statistical analysis A sample size of 51 patients was estimated to give a power of 90% or more to detect any difference between spesolimab and placebo, with response rates estimated at 0.6 and 0.1 for both the primary and major secondary endpoints, respectively, with a type I error (one-sided) of less than 0.025 (which could be considered a type I error of less than 0.05 using two-sided testing). The primary and major secondary endpoints were analyzed using the randomization set with the exact Suissa-Shuster Z-pooled test. This was a one-sided test; two-sided P values ​​were reported by doubling the one-sided P values. Confidence intervals (95% confidence intervals) around the risk difference were calculated using the method of Chan and Zhang for the primary endpoint and all binary secondary endpoints. A fixed order test was used to control for familywise type I error. The primary and key secondary outcomes (both assessed at day 8 [week 1]) were tested hierarchically with a two-sided P level of less than 0.05. If the primary outcome did not reach significance between study arms, the key secondary outcome would not be tested. The protocol and statistical analysis plan called for hierarchical testing of the four subsequent secondary outcomes (GPPASI75 and change from baseline in: pain VAS; PSS; and FACIT-Fatigue), all at week 4; however, randomization to study arm was no longer relevant after week 1. Because 15 of 18 patients assigned to placebo received open-label spesolimab on day 8, missing values ​​were imputed using no response or worst possible outcome.Therefore, comparisons by randomization as originally planned were non-informative, and changes at weeks 1 and 4 for these outcomes are reported narratively by the following groups: all patients randomized to spesolimab (patients who received one or two doses), patients randomized to one dose of spesolimab only (patients who received spesolimab on day 1 only), patients randomized to spesolimab with open-label day 8 spesolimab (patients who were eligible for a second dose on day 8), and patients randomized to placebo with open-label spesolimab on day 8 (patients who received one dose of spesolimab on day 8). For dichotomous outcomes, patients with missing data were considered not to have reached the respective outcome. For continuous outcomes, the last observed case carried forward was used for missing value imputation.

[0268] Post-hoc sensitivity analyses of the primary and key secondary endpoints using linear regression adjusted for baseline imbalanced covariates, including sex, race, and GPPASI, were performed, but no conclusions could be drawn from these data.

[0269] result patient Of 85 patients screened, 53 were enrolled: 35 were assigned to 900 mg spesolimab and 18 to placebo (Figure 1; Table 1). Baseline demographic and disease characteristics differed between groups with respect to the proportion of female participants (60.0% and 83.3% in the spesolimab and placebo groups, respectively) and the proportion of Asian participants (45.7% and 72.2%, respectively). Median baseline GPPASI total score was 27.4 in the spesolimab group and 20.9 in the placebo group (Table 1). At randomization, 18.9% of patients had a GPPGA total score of 4 (severe), and most patients had a GPPGA pustule subscore of 3 or 4 (high or very dense pustules), as well as impaired quality of life and clinical burden as indicated by the Dermatology Life Quality Index (DLQI), pain VAS, FACIT-Fatigue, and PSS (Supplementary Table S3). Seven patients, five in the spesolimab group and two in the placebo group, had IL36RN mutations (Table 1). Most patients did not have CARD14 (38 patients absent) or AP1S3 (42 patients absent) mutations (Supplementary Table S4).

[0270] [Table 24]

[0271] A total of 52 of 53 enrolled patients completed the first week of the study. Data for one patient in the spesolimab group were missing for the primary and key secondary endpoints and were imputed as non-response. On day 8, 12 patients (34.3%) in the spesolimab group and 15 patients (83.3%) in the placebo group received the open-label dose of spesolimab. After day 8, 32 patients (91.4%) initially randomized to spesolimab and 17 patients (94.4%) initially randomized to placebo completed the 12-week follow-up period, during which four and two patients, respectively, required rescue treatment with spesolimab. After completing 12 weeks of treatment, 39 patients entered the open-label extension study (Figure 1).

[0272] Effectiveness Primary and major secondary efficacy endpoints At the end of week 1, 19 patients (54.3%) randomized to spesolimab achieved a GPPGA pustule subscore of 0 (no visible pustules) compared with 1 patient (5.6%) randomized to placebo; (difference, 48.7 percentage points; 95% confidence interval [CI], 21.5 to 67.2; P < 0.001; Table 2, Figure 3A). A GPPGA total score of 0 or 1 (clear or almost clear skin) was achieved in 15 patients (42.9%) randomized to spesolimab compared with 2 patients (11.1%) randomized to placebo at week 1 (difference, 31.7 percentage points; 95% confidence interval, 2.2 to 52.7; P = 0.024; Table 2, Figure 3B). The GPPGA pustule subscore and GPPGA total score over time considering only randomization treatment on day 1 are shown in Figures 4 and 5.

[0273] [Table 25]

[0274] Post-hoc sensitivity analyses of the primary and key secondary endpoints to adjust for observed baseline imbalances in sex, race, and GPPASI were consistent with the primary analysis (Supplementary Tables S5 and S6). Exploratory efficacy endpoints beyond day 8 by randomized treatment on day 1 and open-label spesolimab treatment on day 8.

[0275] After week 1, 15 of 18 patients assigned to placebo received open-label spesolimab on day 8, and thus hierarchical comparison tests of planned secondary endpoints at week 4 were noninformative. Instead, secondary endpoints were reported descriptively by four groups reflecting treatment pathways after day 8: all patients randomized to spesolimab (patients who received one dose [day 1 only] or two doses [days 1 and 8]; N=35), patients randomized to one dose of spesolimab only (day 1; N=23), patients randomized to spesolimab who received open-label day 8 spesolimab (days 1 and 8; N=12), and patients randomized to placebo who received open-label spesolimab on day 8 (N=15). Descriptive analyses for GPPGA pustule subscore of 0 and GPPGA total score of 0 or 1 for these subgroups over time are reported in the Supplementary Information (below) and Figures 6 and 7, and secondary endpoints including change from baseline in GPPASI 75 and below (pain VAS, PSS, and FACIT-Fatigue) at week 4 are reported in the Supplementary Information below.

[0276] Additionally, descriptive results for GPPASI, GPPASI75, pain VAS, DLQI, neutrophil count, and C-reactive protein levels over 12 weeks for the group of patients randomized to spesolimab who received one dose (day 1) or two doses (days 1 and 8; N=35) of spesolimab are reported in Figure 8. Changes from baseline in GPPGA scores (including GPPGA pustule, erythema, and scaling / crusting subscores, and GPPGA total score) in three patients after receiving the first and second doses of spesolimab on days 1 and 8, respectively, are shown in Figure 9.

[0277] safety Adverse events were reported in 65.7% of patients assigned to spesolimab and 55.6% of those in the placebo group throughout the first week of randomization. Fever occurred in 5.7% and 22.2% of patients receiving spesolimab and placebo, respectively; all fever events occurred in the setting of an underlying GPP flare, but drug-causing fever could not be excluded (Table 3). Infections were reported in 17.1% and 5.6% of patients in the spesolimab and placebo groups, respectively, throughout the first week (Supplementary Table S8); there were two cases of urinary tract infections in the spesolimab group and one case each of all other infections during week 1 (see footnotes in Supplementary Table S8). Serious adverse events were reported in 5.7% of patients with spesolimab and none of those receiving placebo.

[0278] [Table 26] TIFF0007662804000042.tif56169

[0279] At week 12, 82.4% of patients who received at least one dose of spesolimab (including patients initially randomized to placebo who received open-label spesolimab on day 8) had an adverse event, and 11.8% had a serious adverse event; in the spesolimab group, the proportion of patients with adverse events remained unchanged or increased, while the time-adjusted incidence rate decreased from week 1 to week 12 (Table 3). Infections were reported in 47.1% of patients; there were three cases each of urinary tract infection and influenza; there were two cases each of the following: folliculitis, otitis externa, upper respiratory tract infection, and pustules; there was one case each of all other infections (see footnotes in Supplementary Table S8). Symptoms observed in two patients receiving spesolimab were reported as drug reaction with eosinophilia and systemic symptoms (DRESS), with RegiSCAR scores of 1 and 3.33. Further details of these two case reports can be found in the supplementary information below. Anti-drug antibodies (ADA) were detected at a median time of 2.3 weeks after administration of spesolimab. ADA was detected in 23 of 50 (46%) patients who received at least one dose of spesolimab. The majority (87%) of ADA-positive patients (40% of total treated) were also neutralizing antibody (Nab)-positive, and NAb status appeared to be associated with titer values. No dose-dependency was observed; however, surprisingly, maximum ADA titers appeared to be decreased in GPP patients (n=4!) who received 2 doses by day 8 versus only 1 dose.

[0280] Consideration This randomized trial of a single intravenous dose of spesolimab, a humanized anti-IL-36 receptor monoclonal antibody, in patients with GPP flare showed better lesion clearance compared with placebo at week 1. Overall, infections were more frequent with spesolimab, but there was no clear pattern regarding pathogen and affected organs, and two patients treated with spesolimab had drug reactions with eosinophilia and systemic symptoms, indicating RegiSCAR scores of 1 and 3.

[0281] At the end of the randomized 1-week period, one-third of the patients in the spesolimab group and the majority of patients in the placebo group received open-label spesolimab and were followed up for 12 weeks. Because 15 of 18 randomized placebo patients received open-label spesolimab, the true effect of spesolimab versus placebo could not be reflected in this study beyond the first week. This highlights one of the inherent challenges of conducting a randomized placebo-controlled study in patients with this disease; the suddenness and severity of GPP flares (potentially life-threatening) presents several challenges in the study design, including limiting the duration for which patients can ethically be scheduled to receive placebo treatment in this study; furthermore, the clinical course is heterogeneous and can be characterized as a relapsing disease with recurrent flares or as a persistent disease with intermittent flares, making it difficult to select the appropriate time for study endpoints.

[0282] As noted above, this study has limitations, including a small number of enrolled patients (typical for rare diseases); however, effect sizes for the primary and key secondary endpoints at week 1 were large and significant. The randomization period was limited to 1 week, and patients' option to receive open-label treatment with spesolimab at week 1 if the prespecified severity thresholds were still met meant that most placebo patients received spesolimab, and thus comparative analyses beyond week 1 were uninformative; therefore, hierarchical testing of the secondary endpoints defined at week 4 was not reported here. There were some baseline imbalances (gender, race, and GPPASI) between the randomized treatment groups; however, post-hoc sensitivity analyses of the primary and key secondary endpoints adjusted for imbalances were consistent with the primary analysis.

[0283] Despite these challenges, the rapid control of flare development in this study with a single infusion of spesolimab builds on findings from previous open-label spesolimab studies and supports the hypothesis that IL-36 is a central trigger in the pathogenesis of GPP. Improvements over time in measures including C-reactive protein, neutrophil count, pain, PSS, FACIT-Fatigue, and DLQI indicate that spesolimab acts systemically beyond the skin and suggest that spesolimab has the potential to improve quality of life in patients experiencing GPP flares. Chronic administration of spesolimab is being evaluated using a subcutaneous formulation in an ongoing 5-year open-label extension study (ClinicalTrials.gov Identifier: NCT03886246) and in the flare prevention study Effisayil2 (ClinicalTrials.gov Identifier: NCT04399837).

[0284] In conclusion, in this phase 2 study, GPP flares treated with intravenous spesolimab resulted in a higher rate of pustular lesion clearance compared with placebo, but were associated with infections and systemic reactions. Longer and larger studies are needed to determine the efficacy and safety of spesolimab in GPP.

[0285] Supplementary Information Physician Global Assessment (GPPGA) for Generalized Pustular Psoriasis The GPPGA relies on clinical assessment of the patient's skin symptoms. It is a modified Physician's Global Assessment (PGA), a physician's assessment of psoriatic lesions adapted to the evaluation of patients with generalized pustular psoriasis (GPP). The investigator (or a qualified site investigator) scores the erythema, pustules and scale of all psoriatic lesions from 0 to 4 (see table below). Each component is graded separately, the average is calculated and the final GPPGA is determined from this composite score (composite average score = (erythema + pustules + scale) / 3; a GPPGA total score of 0 means 0 for all three components, a score of 1 means 0 to less than 1.5, a score of 2 means 1.5 to less than 2.5, a score of 3 means 2.5 to less than 3.5 and a score of 4 means 3.5 or greater). Lower scores indicate lower severity, with 0 relating to "clear" and 1 to "almost clear". In order to receive a score of 0 or 1, patients must be afebrile in addition to the requirement of skin symptoms.

[0286] Generalized Pustular Psoriasis Area and Severity Index (GPPASI) GPPASI is an adaptation of PASI, a measure of the severity and area of ​​psoriatic lesions established in psoriasis patients, for GPP patients. A similar adaptation is used for palmoplantar psoriasis. In GPPASI, the induration component is replaced by the pustule component. It is an instrument that provides a numerical score for the patient's overall generalized pustular psoriasis disease status, ranging from 0 to 72. It is a linear combination of the proportion of skin surface area affected (body area score) and the severity of erythema, pustules, and scaling (peeling) on ​​four body regions (head, upper limbs, trunk, and lower limbs) (scored on a 5-point scale ranging from 0 [least severe] to 4 [most severe]).

[0287] [Table 27]

[0288] Inclusion and Exclusion Criteria Selection Criteria Patients will be enrolled (screened) into the study if they meet the following criteria: Patients with a GPPGA score of 1a.0 or 1 and a known and documented history of GPP (per ERASPEN criteria) regardless of IL36RN mutation status, and who also had previous fever and / or asthenia, and / or myalgia, and / or elevated C-reactive protein, and / or leukocytosis with peripheral blood neutrophilia (above the upper limit of normal [ULN]); 1b. Patients with a flare of moderate to severe intensity meeting the ERAPEN criteria for GPP, with a known and documented history of GPP (per ERASPEN criteria) regardless of IL36RN mutation status, and with fever, and / or asthenia, and / or myalgia, and / or elevated C-reactive protein, and / or leukocytosis (above the upper limit of normal) with peripheral blood neutrophilia, or Patients experiencing their first episode of a GPP flare of moderate to severe intensity with evidence of fever, and / or asthenia, and / or myalgia, and / or elevated C-reactive protein, and / or leukocytosis (above the upper limit of normal) with peripheral blood neutrophilia. The diagnosis for these patients will be confirmed retrospectively by a central external expert / committee. 2. Patients may or may not be receiving background treatment with retinoids and / or methotrexate and / or cyclosporine. Patients must discontinue retinoids / methotrexate / cyclosporine prior to receiving the first dose of spesolimab or placebo. 3.Male or female patients aged 18-75 years at the time of screening. 4. Signed and dated written informed consent prior to the start of any screening procedures and prior to approval of the clinical trial in accordance with ICH-GCP and local ministerial regulations. 5. Women of childbearing potential must be prepared and able to use highly effective contraceptive methods per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Women are considered women of childbearing potential (WOCBP), i.e., fertile after menarche until postmenopause, unless permanently infertile. Permanent contraceptive methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is not a permanent method of contraception. The postmenopausal state is defined as the absence of menstruation for 12 months without alternative medical causes.

[0289] Exclusion criteria Patients will not be screened or treated if any of the following criteria apply: 1. Patients with synovitis-acne-pustulosis-osseosis-osteitis syndrome. 2. Patients with primary erythrodermic plaque psoriasis. 3. Patients with primary plaque-type psoriasis vulgaris without the presence of pustules or with pustules localized to the psoriatic plaques. 4. Drug-triggered acute generalized exanthematous pustulosis. 5. Immediate life-threatening flare of GPP or requiring intensive care treatment as determined by the investigator. Life-threatening complications include but are not limited to cardiovascular / cytokine-induced shock, pulmonary distress syndrome, or renal failure. 6. Severe, progressive, or uncontrolled liver disease defined as elevation of aspartate transaminase or alanine transaminase or alkaline phosphatase more than 3 times the upper limit of normal, or elevation of total bilirubin more than 2 times the upper limit of normal. 7.a. Treatment with any restricted medication, or any medication that may interfere with the safe conduct of the study as assessed by the investigator. b. Treatment with any prior exposure to spesolimab or another IL36R inhibitor. 8. Patients using escalating doses of cyclosporine and / or methotrexate and / or retinoids for maintenance therapy within 2 weeks prior to receiving the first dose of spesolimab / placebo. 9. Initiation of systemic medications such as cyclosporine and / or retinoids and / or methotrexate 2 weeks prior to receiving the first dose of spesolimab / placebo. 10. Patients with congestive heart disease, as assessed by the investigator. 11. Active systemic infection (fungal and bacterial diseases) within the last 2 weeks prior to receiving the first drug dose as assessed by the investigator. 12. Elevated risk of infectious complications (e.g., recent febrile infection, any congenital or acquired immunodeficiency disease [e.g., human immunodeficiency virus (HIV)], previous solid organ or stem cell transplant) as assessed by the investigator. 13. Associated chronic or acute infection, including HIV or hepatitis virus. For patients who have a flare but are screened (selection criteria 1b or 1c), if HIV or hepatitis virus results from Visit 1 are not available at the time of randomization, these patients may receive randomized treatment as long as the investigator rules out active disease based on available recorded medical history (i.e., negative HIV and hepatitis virus test results) within 3 months prior to Visit 2. If the patient is treated and cured of acute infection, the patient may be screened again. 14. Active or Latent Tuberculosis (TB): QuantiFERON® (or T-Spot®, if applicable) TB testing will be performed at screening. If the result is positive, the patient may enter the trial if further testing (following local practice / guidelines) conclusively establishes that the patient has no evidence of active TB. Patients with active TB must be excluded. If the presence of latent TB is established, then treatment should be initiated and maintained according to local country guidelines. For patients who have a flare but are screened (inclusion criteria 1b or 1c), if TB test results are not available in time for randomization, these patients may receive randomization treatment (provided they meet all other inclusion / exclusion criteria) as long as the investigator rules out active disease based on available recorded medical history (i.e. negative for active TB) within 3 months prior to the second visit. 15. History of allergy / hypersensitivity to any systemically administered investigational drug or its excipients. 16. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except adequately treated basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia. 17.Currently participating in another investigational device or drug study, or less than 30 days since completing another investigational device or drug study(s) or receiving another investigational treatment(s). 18. Females who are pregnant, breastfeeding, or planning to become pregnant during the study. Women who discontinue breastfeeding prior to administration of study drug need not be excluded from participation; however, women should refrain from breastfeeding until 16 weeks after administration of study drug. 19. Major surgery (major surgery as assessed by the investigator) performed within 12 weeks prior to receiving the first dose of investigational drug or planned during the study, e.g., hip replacement, aneurysm removal, gastric ligation, as assessed by the investigator. 20. Evidence of current or previous disease, medical condition outside the GPP (including chronic alcohol or drug abuse or any condition), surgery, mental or social problems, physical examination findings (including vital signs and ECG), or screening laboratory values ​​outside the reference range that, in the opinion of the investigator, are clinically significant and make the study participant unreliable to follow the protocol, comply with all study visits / procedures, or complete the study, compromising patient safety, or compromising the quality of the data.

[0290] [Table 28] TIFF0007662804000045.tif20169

[0291] [Table 29]

[0292] [Table 30]

[0293] [Table 31]

[0294] Exploratory efficacy endpoints beyond day 8, with randomized treatment on day 1 and open-label spesolimab treatment on day 8. Descriptive analysis of GPPGA pustular subscore of 0 and GPPGA total score of 0 or 1 by the four groups.

[0295] In patients initially randomized to spesolimab (N=35), who received spesolimab on day 1 with or without open-label spesolimab on day 8, at the end of week 1, 19 patients (54%) achieved a GPPGA pustular subscore of 0 and 15 patients (43%) achieved a GPPGA total score of 0 or 1; at week 12, 21 patients (60%) had a GPPGA pustular subscore of 0 and a GPPGA total score of 0 or 1 (Figures 5 and 6). Among the 23 patients randomized to spesolimab who did not receive open-label spesolimab on day 8, 19 (83%) achieved a GPPGA pustule subscore of 0 and 15 (65%) achieved a GPPGA total score of 0 or 1 at the end of week 1; at week 12, these scores were reported in 15 (65%) and 16 (70%) patients, respectively (Figures 5 and 6). Among patients (N=12) initially randomized to spesolimab who received open-label spesolimab on day 8, at the end of week 2, 5 patients (42%) achieved a GPPGA pustule subscore of 0 and 2 patients (17%) achieved a GPPGA total score of 0 or 1; at week 12, 6 patients (50%) and 7 patients (58%) had a GPPGA pustule subscore of 0 and a GPPGA total score of 0 or 1 (Figures 5 and 6). Among 15 patients in the placebo group who received open-label spesolimab on day 8, at the end of week 2 (7 days after open-label spesolimab), 11 (73%) achieved a GPPGA pustule subscore of 0 and 8 (53%) achieved a GPPGA total score of 0 or 1; at week 12, these scores were reported in 6 (40%) and 8 (53%) patients, respectively (Figures 5 and 6).

[0296] Descriptive analysis of planned GPPASI75 hierarchical secondary endpoints and change from baseline in pain VAS; PSS; and FACIT-Fatigue at week 4 by the four groups For GPPASI 75 at week 4, 18 of 35 (51%) patients initially randomized to spesolimab who received spesolimab on day 1 with or without open-label spesolimab on day 8 achieved GPPASI 75. Among 23 patients randomized to spesolimab who did not receive open-label spesolimab on day 8, 16 (70%) achieved GPPASI 75 at week 4 (Supplementary Table S7). Among 12 patients in the spesolimab group and 15 patients in the placebo group who received an open-label dose of spesolimab at the end of week 1, 2 (17%) and 6 (40%) patients, respectively, achieved GPPASI 75 at week 4 (Supplementary Table S7).

[0297] For pain VAS at week 4, in patients initially randomized to spesolimab who received spesolimab on day 1 with or without open-label spesolimab on day 8, the median (interquartile range; IQR) change from baseline was -53.4 (-77.8, -20.2) (Supplementary Table S7). Among the 23 patients randomized to spesolimab who did not receive open-label spesolimab on day 8, the median (IQR) change from baseline was -63.1 (-79.8, -22.5). Among the 12 patients in the spesolimab group and the 15 patients in the placebo group who received the open-label dose of spesolimab, the median (IQR) change from baseline was −44.6 (−71.2, −17.3) and −54.3 (−79.0, 33.3), respectively (Supplementary Table S7).

[0298] For PSS at week 4, among patients initially randomized to spesolimab who received spesolimab on day 1 with or without open-label spesolimab on day 8, the median (IQR) change from baseline was -7.0 (-10.0, -3.0) (Supplementary Table S7). Among the 23 patients randomized to spesolimab who did not receive open-label spesolimab on day 8, the median (IQR) change from baseline was -7.0 (-11.0, -2.0). Among the 12 patients in the spesolimab group and the 15 patients in the placebo group who received the open-label dose of spesolimab, the median (IQR) change from baseline was -6.0 (-7.0, -3.5) and -5.0 (-9.0, -2.0), respectively (Supplementary Table S7).

[0299] For FACIT-Fatigue at week 4, among patients initially randomized to spesolimab who received spesolimab on day 1 with or without open-label spesolimab on day 8, the median (IQR) change from baseline was 22.0 (1.0, 31.0) (Supplementary Table S7). Among the 23 patients randomized to spesolimab who did not receive open-label spesolimab on day 8, the median (IQR) change from baseline was 22.0 (3.0, 35.0) (Supplementary Table S7). Among the 12 patients in the spesolimab group and the 15 patients in the placebo group who received the open-label dose of spesolimab, the median (IQR) change from baseline was 15.0 (5.5, 28.5) and 16.0 (-19.0, 26.0), respectively (Supplementary Table S7).

[0300] [Table 32] TIFF0007662804000050.tif218169 TIFF0007662804000051.tif43169

[0301] Descriptive analysis of GPPASI, GPPASI75, pain VAS, DLQI, neutrophil count, and C-reactive protein levels by patient group randomized to spesolimab who received one dose (day 1) or two doses (days 1 and 8):

[0302] The median % improvement in GPPASI score from baseline was 43% at week 1 and progressively increased to 82% at week 12 (Figure 7A). GPPASI 75 was achieved in 13 (37%) patients at week 2, 18 (51%) patients at week 4, 21 (60%) patients at week 8, and 20 (57%) patients at week 12 (Figure 7B). Rapid reduction in pain VAS scores and improvement in DLQI scores were achieved from week 4 to week 12 (Figures 7C and 7D). In patients with baseline elevated neutrophil counts normalized within 1 week of receiving spesolimab (Figure 7E). Median C-reactive protein (CRP) normalized within 2 weeks in patients with baseline elevated CRP (≥10 mg / L) who received 1 or 2 doses of spesolimab (Figure 7F).

[0303] [Table 33]

[0304] Example 2 Treatment with spesolimab improves pain, psoriasis symptoms, fatigue, and quality of life in patients with generalized pustular psoriasis: Patient-reported outcomes results from the Effisayil 1 trial Introduction and Objectives: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease characterized by widespread sterile pustules and recurrent flares. Signs and symptoms associated with GPP include pain, fever, and fatigue, which can affect activities of daily living and overall quality of life (QoL). Spesolimab has been reported to rapidly improve pustule and skin clearance in patients with GPP flares. The objective of this analysis was to evaluate patient-reported outcomes (PROs) regarding pain measures, psoriasis symptoms, fatigue, and impact on overall quality of life in patients treated with spesolimab from the Effisayil1 study.

[0305] Materials and Methods: Effisayil1 (NCT03782792) was a multicenter, randomized, double-blind, placebo-controlled trial in patients with GPP flare. Eligible patients (n=53) were randomly assigned (2:1) to receive a single open-label 900 mg intravenous (IV) dose of spesolimab or placebo on day 1 and followed for 12 weeks. At week 1, patients were eligible to receive a single open-label 900 mg IV dose if they had a Physician's Global Assessment for GPP (GPPGA) score of 2 or higher and had not received escape medication before day 8. Secondary and higher-level outcomes were assessed over time through the end of the study using the Psoriasis Symptom Scale (PSS; 0-16, higher scores indicating more severe symptoms), Pain Visual Analog Scale (Pain VAS; 0 [no pain] to 100 [severe pain]), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue; 0-52, lower scores indicating greater impact), and Dermatology Quality of Life Index (DLQI: 0 [no effect] to 30 [extreme effect]). Patients who received escape treatment (any standard of care treatment administered to patients within 1 week of their first dose) or rescue medication (any 900 mg intravenous dose of spesolimab administered any time after day 8) were considered non-responders at later time points in the analysis.

[0306] Results: Patients were randomized to receive 900 mg of spesolimab (n=35) or placebo (n=18). At baseline, patients had a high clinical burden and impaired quality of life as indicated by median PSS (11.0), pain VAS (79.8), FACIT-Fatigue (14.0), and DLQI (19.5) scores (Table 9). Improvements in PSS, pain VAS, FACIT-Fatigue, and DLQI scores were observed from baseline to week 12 (Table). Pain improved as early as week 1, further improved at week 4, and was maintained through week 12. For other patient-reported outcomes (PSS, FACIT-Fatigue, and DLQI), improvements were also seen as early as week 1, but continued to improve through week 12.

[0307] Conclusions: Patients receiving 900 mg of spesolimab (intravenously) and an optional second dose on day 8 showed significant improvements in patient-reported outcomes of pain, pain symptoms, fatigue, and overall quality of life. These improvements were seen early and were maintained through week 12. These findings suggest that up to two doses of spesolimab can result in rapid clearance of GPP flares, which is accompanied by improved patient-reported outcomes.

[0308] [Table 34]

[0309] Example 3 Treatment with spesolimab improves pain, psoriasis symptoms, fatigue and quality of life in patients with generalized pustular psoriasis: Patient-reported outcomes from the Effisayil 1 study Objective: To evaluate patient-reported outcomes regarding pain measures, psoriasis symptoms, fatigue, and impact on overall quality of life (QoL) in patients treated with spesolimab in the Effisayil™ 1 study.

[0310] Introduction: GPP is a rare and potentially life-threatening neutrophilic skin disease characterized by widespread eruption of sterile visible pustules, which may occur with or without systemic inflammation. In the multicenter, randomized, double-blind, placebo-controlled Effisayil™ 1 study (NCT03782792) in patients with GPP flare, treatment with spesolimab resulted in rapid pustule resolution and skin clearance within 1 week. GPP flare is associated with a high clinical burden in patient-reported outcomes, including symptoms such as pain, itch, and fatigue, all of which affect the patient's overall quality of life. Here we explore patient-reported outcomes in patients with GPP flare treated with spesolimab.

[0311] METHODS: Patients (N=53) were randomized (2:1) to receive placebo or 900 mg spesolimab on day 1 and followed for 12 weeks. Patients could receive standard of care (SoC) treatment any time after receiving the initial dose of spesolimab or placebo on days 1 and before day 8. Patients who did not receive standard of care treatment during the first week were eligible to receive open-label (OL) spesolimab on day 8 and one rescue dose of open-label spesolimab from days 8 through week 12.

[0312] Spesolimab group (n=35): 1 dose of spesolimab on day 1 (n=23); optional 2nd dose of open-label spesolimab on day 8 (n=12); optional 3rd dose of open-label spesolimab from weeks 1 to 12 (n=2).

[0313] Placebo group (n=18): open-label spesolimab with optional first dose on day 8 (n=15); open-label spesolimab with optional second dose from weeks 1 to 12 (n=1).

[0314] Patients who had already received their one rescue dose of spesolimab were treated with escape treatment (standard of care) for any subsequent flare. All randomized patients were included in this analysis. Cases observed regardless of the use of either escape treatment, open-label spesolimab on day 8, or rescue treatment with spesolimab after day 8 (demonstrating the intention-to-treat principle) are summarized descriptively. To monitor any changes in outcomes, patients completed the following patient-reported outcome questionnaires during the study: Psoriasis Symptom Scale [PSS], Pain Visual Analog Scale (Pain VAS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Dermatology Quality of Life Index (DLQI; Figure 10). All four patient-reported outcomes were measured on day 1, day 8, and weeks 2-4, 8, and 12. PSS scores were also measured daily during week 1 (days 4-7 data not shown).

[0315] Conclusions: In this study, patients receiving 900 mg of spesolimab intravenously demonstrated clinically significant improvements from baseline in patient-reported outcomes of pain, psoriasis symptoms, fatigue, and overall quality of life. Clear separation of the spesolimab and placebo curves occurred early during the placebo-controlled period (week 1) (Figure 11). This suggests that spesolimab produces rapid improvements in patient-reported outcomes, along with substantial improvements in fatigue and pain. Patient-reported outcome scores continued to improve by week 4 and were sustained through week 12 (Figure 11).

[0316] Example 4 Sustained treatment efficacy of spesolimab over 12 weeks for flares of generalized pustular psoriasis: results from the Effisayil-1 trial The aim of this study was to analyze the efficacy of spesolimab over a 12-week period for the treatment of patients with a flare of generalized pustular psoriasis.

[0317] In a double-blind, randomized, placebo-controlled study of Effisayil™ 1 in patients with flares of generalized pustular psoriasis (GPP), a rare and life-threatening autoimmune disease, spesolimab, an anti-IL-36 receptor antibody, led to rapid clearance (within 1 week) of pustules and skin lesions. Here, we explore the effect of spesolimab over the 12-week period of the study (intention-to-treat analysis).

[0318] Patients (n=53) were randomized to receive a single 900 mg intravenous dose of spesolimab (n=35) or placebo (n=18) on day 1. On day 8, patients were eligible to receive an open-label dose of spesolimab if they had persistent symptoms; 12 (34.3%) in the spesolimab group and 15 (83.3%) in the placebo group. Among patients (n=35) initially randomized to spesolimab who received up to two doses, 61.8% and 84.4% achieved a GPPGA pustular subscore of 0, and 50.0% and 81.3% achieved a GPPGA total score of 0 / 1 at weeks 1 and 12, respectively. Among patients initially randomized to placebo who received open-label spesolimab on day 8, 83.3% and 80.0% had a GPPGA pustular subscore of 0 and 93.3% had a GPPGA total score of 0 / 1 by week 2 (1 week after spesolimab) and week 12, respectively. After day 8, 32 and 17 patients randomized to spesolimab and placebo, respectively, completed the 12-week follow-up period, during which time 4 and 2 patients required rescue treatment with spesolimab for the development of a new flare.

[0319] Spesolimab demonstrated rapid and sustained clinical improvement over 12 weeks. These data further support spesolimab as a potential treatment option for patients with GPP flare.

[0320] Example 5 Results of Clinical Immunogenicity Evaluation - Study 1368-0013: A study of spesolimab (BI655130) in patients with flare-ups of a skin disease called generalized pustular psoriasis Analytical methods: Blood samples for the evaluation of anti-drug / neutralizing antibodies were collected from subjects (patients) before and during the course of treatment with spesolimab, and at the end / discontinuation of the study. All samples were first analyzed in the anti-drug antibody screening assay, and only those found to be presumptively positive were subsequently evaluated in the anti-drug antibody confirmatory assay. Only confirmed positive samples were titrated to obtain titration values. Furthermore, the development of neutralizing antibodies was evaluated only in subjects with anti-drug antibody positive samples.

[0321] The immunogenicity assessment of spesolimab was performed using data from all evaluable subjects, defined as subjects with a baseline immunogenicity assessment and at least one post-baseline value. For subjects treated with spesolimab, the baseline sample was considered the last sample obtained before the start of active treatment. For patients not treated with spesolimab, the baseline sample was the last sample obtained before receiving placebo treatment.

[0322] Background: This was a randomized, placebo-controlled, double-blind, parallel-group, single-dose study with two treatment arms (spesolimab 900 mg intravenously on day 1 and placebo). Patients could be eligible to receive open-label (OL) treatment with 900 mg intravenous spesolimab on day 8 and rescue treatment with spesolimab after day 8, depending on their GPPGA total score and GPPGA pustule subscore. Patients were offered to proceed to the open-label extension (OLE) study 1368-0025 if they met the inclusion criteria for this open-label extension study. The follow-up period for study 1368-0013 was 12 to 28 weeks, depending on the timing of the last spesolimab dose in study 1368-0013 and whether patients continued in the open-label extension study.

[0323] A total of 53 male and female patients with GPP were randomized in a 2:1 ratio to receive a single dose of 900 mg intravenous spesolimab (35 patients) or placebo (18 patients) on day 1. Spesolimab as an open-label dose on day 8 was administered to 27 patients overall and to a total of 6 patients after day 8 as rescue medication.

[0324] More female patients (N = 36) than male patients (N = 17) were randomized. All patients were Asian (N = 29) or Caucasian (N = 24) ethnicity. The mean (SD) age was 43.0 (10.9) years, and the mean (SD) weight was 72.0 (24.7) kg.

[0325] Pharmacokinetic and anti-drug / neutralizing antibody samples were collected predose, day 4, weeks 1, 2, 3, 4, and 8, and at end of study. For patients who did not enter the open-label extension 1368-0025 study, the end of study visit was 16 weeks after the last spesolimab dose. For patients who entered the open-label extension study, the end of study visit was week 12, or 6 weeks after the last dose if the patient received a rescue dose between weeks 7 and 12.

[0326] Anti-drug antibody / neutralizing antibody (ADA / Nab) response: In study 1368-0013, of the 53 randomized patients, 2 patients randomized to placebo on day 1 did not receive any spesolimab treatment during the study. All anti-drug antibody samples from these 2 patients were negative. Of the 51 spesolimab-treated patients, 50 patients were evaluable for anti-drug antibodies with available pre- and post-baseline anti-drug antibody assessments, including 1 patient who received placebo on day 1 and open-label rescue spesolimab on or after day 8. All 50 anti-drug antibody-evaluable patients were anti-drug antibody negative at baseline.

[0327] The incidence of anti-drug antibody positive patients observed in 1368-0013 is comparable to that in the proof-of-concept study 1368-0011. Overall, 23 (46%) of 50 anti-drug antibody evaluable patients treated with spesolimab were anti-drug antibody positive after treatment, and 27 patients (54%) were anti-drug antibody negative during the study period. Twelve patients (24%) had a maximum titer greater than 4000. The majority (87%) of anti-drug antibody positive patients (40% of the total treated) were also neutralizing antibody positive, and neutralizing antibody status appeared to be related to titer value. All anti-drug antibody samples with titer values ​​greater than 4000 were neutralizing antibody positive. Of the anti-drug antibody samples with titer values ​​less than 4000, some were neutralizing and others were not. The lower the titer value, the more likely the anti-drug antibody sample was to be neutralizing antibody negative. In anti-drug antibody positive patients, anti-drug antibodies developed early, with a median time to onset of 2.3 weeks, and reached maximum titers at a median time of 11.7 weeks. In approximately 75% of patients, maximum titers occurred in the last sample collected. The time to maximum anti-drug antibody titers and the titers themselves may be affected by the duration of the study and the time of collection. In neutralizing antibody positive patients, neutralizing antibodies were detected with a median time to onset of 6.7 weeks. At the end of the study (12-17 weeks after the effective first dose), anti-drug antibodies had resolved in 4 of 23 anti-drug antibody positive patients. Nineteen patients (38% of the total evaluable anti-drug antibodies) were still anti-drug antibody positive, 18 (36%) patients were still neutralizing antibody positive, and 12 (24%) patients had titers >4000.

[0328] The incidence of anti-drug antibodies was similar between patients treated with one dose of spesolimab and those who received two doses. However, maximum anti-drug antibody titers were observed to be lower in patients who received two doses of intravenous spesolimab within the first 8 days (days 1 and 8) compared to patients who received only one intravenous dose (Table 10, Figure 12).

[0329] [Table 35]

[0330] Furthermore, women appeared to have a higher immunogenic response. The incidence of anti-drug antibodies was 58% and 24% in women and men, respectively. The proportion of patients with maximum titers over 4000 was 30% in women compared to 12% in men (Table 11). Given the small number of anti-drug antibody positive male patients, there does not appear to be any significant difference in maximum titers between the sexes.

[0331] [Table 36]

[0332] Relationship between efficacy and treatment-emergent anti-drug / neutralizing antibodies For the analysis, anti-drug antibody titer groups were defined based on tertiles of maximum anti-drug antibody titers among patients. The maximum anti-drug antibody titer observed in the study was used to distinguish three groups based on maximum anti-drug antibody titers ([percentile below 33.3%, 1440], [percentile above 33.3% and below 66.6%], and [percentile above 66.6%, 43200]). Furthermore, anti-drug antibody vs efficacy analysis distinguished between neutralizing antibody negative and neutralizing antibody positive patients. For patients included in the neutralizing antibody negative group, all samples were neutralizing antibody negative or anti-drug antibody negative. Patients included in the neutralizing antibody positive group had at least one sample that was neutralizing antibody positive.

[0333] In general, in study 1368-0013, the proportion of patients with a GPPGA pustule subscore of 0 or a GPPGA total score of 1 over time was similar for anti-drug antibody negative and anti-drug antibody positive patients. When patients were classified according to tertiles as defined above, the response rate over time was generally similar between all three titer groups. Therefore, in general, this also applies when patients are categorized by having a titer value of less than 4000 and more than 4000. At week 12, the response rate appears to decrease for patients with a titer value of more than 43200. From the eight patients with a titer value of more than 43200, four showed a decrease in their respective scores, while the other four did not. The decrease in response rate was not very strong for the score itself, since three out of four patients showed an increase of only one point.

[0334] Example 6 Treatment with spesolimab improves CGI scores via the Japanese Dermatological Association Severity Index in patients with GPP. In the Effisayil1™1 study, patients with a flare of generalized pustular psoriasis (GPP) achieved disappearance of pustules and skin clearance after receiving spesolimab. We report the change from baseline in the Japanese Dermatological Association Severity Index Clinical Global Impression (CGI) score at week 1. Patients (N=53) were randomly assigned (2:1) to receive 900 mg of spesolimab or placebo intravenously on day 1 and followed for 12 weeks. In the spesolimab group (n=31), 67.7% of patients saw improvement (score 1-3) and 32.3% saw no improvement at all (score 4-5). In the placebo group (n=15), 53.3% of patients saw improvement and 46.7% saw no improvement at all. A score of 1 (very much improved) was achieved by 76.2% of spesolimab improvers. In conclusion, treatment with spesolimab improved the Japanese Dermatological Association Clinical Global Impression score in patients with GPP flares compared with placebo.

[0335] While specific aspects and embodiments of the invention have been described, they are offered by way of example only and are not intended to limit the scope of the invention. Indeed, the novel methods and systems described herein may be embodied in a wide variety of other forms without departing from the spirit thereof. The accompanying claims and their equivalents are intended to cover such forms or modifications as fall within the scope and spirit of the invention.

[0336] All patents and / or publications, including journal articles, cited in this disclosure are expressly incorporated herein by reference.

Claims

1. A pharmaceutical composition comprising an anti-IL-36R antibody for treating a generalized pustular psoriasis (GPP) flare in a patient, wherein the anti-IL-36R antibody is spesolimab and is administered to the patient in two 900 mg intravenous (iv) doses, wherein the second dose is administered less than two weeks after the first dose.

2. A pharmaceutical composition comprising an anti-IL-36R antibody for treating GPP in a patient, wherein the anti-IL-36R antibody is spesolimab and is administered to the patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

3. 1. A pharmaceutical composition for reducing or alleviating signs and symptoms of an acute flare-up of GPP in a patient, comprising an anti-IL-36R antibody, wherein the anti-IL-36R antibody is spesolimab and is administered to the patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

4. A pharmaceutical composition comprising an anti-IL-36R antibody for reducing the severity and duration of symptoms of GPP, wherein the anti-IL-36R antibody is spesolimab and is administered to a patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

5. A pharmaceutical composition containing an anti-IL-36R antibody for improving GPPGA pustule subscore for skin disorders associated with GPP in a patient, wherein the anti-IL-36R antibody is spesolimab and is administered to the patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

6. A pharmaceutical composition for preventing recurrence of GPP flare in a patient, comprising an anti-IL-36R antibody, wherein the anti-IL-36R antibody is spesolimab and is administered to the patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

7. A pharmaceutical composition for improving pain in a patient with GPP, comprising an anti-IL-36R antibody, a pharmaceutical composition, wherein the anti-IL-36R antibody is spesolimab, the pain is measured by a visual analog scale (VAS) score for pain, and the improvement is a decrease of at least 10% in the VAS score after administration of the anti-IL-36R antibody compared to the patient's baseline VAS score prior to administration, and the patient is administered two 900 mg intravenous doses of the anti-IL-36R antibody, wherein the second dose is administered less than two weeks after the first dose.

8. A pharmaceutical composition comprising an anti-IL-36R antibody for improving quality of life in a patient with moderate to severe GPP symptoms, wherein the anti-IL-36R antibody is spesolimab, and the quality of life in the patient is measured by a Skin Disease Quality of Life Index (DLQI), and the improvement is a decrease of at least 10% in DLQI after administration of the anti-IL-36R antibody compared to the patient's baseline DLQI before administration, and wherein the anti-IL-36R antibody is administered to the patient in two 900 mg intravenous doses, wherein the second dose is administered less than two weeks after the first dose.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the patient has a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the patient has a GPPGA total score of 2 or greater and a GPPGA pustular subscore of 2 or greater.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the patient has a GPPGA total score of 2 or greater and a GPPGA pustule subscore of 2 or greater prior to administration of the first intravenous dose.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the patient has a GPPGA total score of 2 or greater and a GPPGA pustule subscore of 2 or greater after administration of the first intravenous dose.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the patient has a GPPGA total score of 2 or greater and a GPPGA pustule subscore of 2 or greater before and after administration of the first intravenous dose.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the second dose is administered one week but no earlier than two weeks after the first dose.

15. 1. A pharmaceutical composition comprising an anti-IL-36R antibody for treating a GPP patient with a GPPGA pustular subscore of 2 or greater, wherein the anti-IL-36R antibody is spesolimab, (a) the patient is administered an initial 900 mg intravenous (iv) dose of the anti-IL-36R antibody; and (b) the patient's GPPGA pustular subscore is assessed, and if the patient's GPPGA pustular subscore of 2 or greater persists one week after the first dose, then the patient is administered a second 900 mg (iv) dose of the anti-IL-36R antibody less than two weeks after the first dose.

16. 1. A pharmaceutical composition comprising an anti-IL-36R antibody for treating a GPP patient with a GPP Physician's Global Assessment (GPPGA) total score of 2 or greater, wherein the anti-IL-36R antibody is spesolimab, (a) the patient is administered an initial 900 mg intravenous (iv) dose of the anti-IL-36R antibody; and (b) the patient's GPPGA total score is assessed, and if the patient's GPPGA total score of 2 or greater persists one week after the first dose, then the patient is administered a second 900 mg (iv) dose of the anti-IL-36R antibody less than two weeks after the first dose.

17. 1. A pharmaceutical composition comprising an anti-IL-36R antibody for treating a GPP patient having a GPPGA total score of 2 or greater and a GPPGA pustular subscore of 2 or greater, wherein the anti-IL-36R antibody is spesolimab, (a) the patient is administered an initial 900 mg intravenous (iv) dose of the anti-IL-36R antibody; and (b) the patient's GPPGA score is assessed, and if the patient's GPPGA total score of 2 or greater and GPPGA pustular subscore of 2 or greater persists one week after the initial dose, then the patient is administered a second 900 mg (iv) dose of the anti-IL-36R antibody less than two weeks after the initial dose.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein an optional third 900 mg intravenous dose of the anti-IL-36R antibody is administered 2 to 12 weeks after the second intravenous dose.

19. The two doses are administered as follows: (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) Pustule subscore of 0, presented 1 week after administration of the second intravenous dose; (b) a GPPGA total score of 0 or 1 one week after administration of the second intravenous dose; and / or (c) a lower maximum titer of anti-drug antibodies at weeks 2, 4, 6, 8, 10, or 12 after administration of the second intravenous dose. The pharmaceutical composition according to any one of claims 1 to 18, which achieves one or more of the following results:

20. 20. The pharmaceutical composition of claim 19, wherein the results are maintained for up to and at least 12 weeks after administration of the second intravenous dose.

21. The pharmaceutical composition of any one of claims 1 to 20, further comprising administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses after the final intravenous dose has been administered.

22. 22. The pharmaceutical composition of claim 21, wherein each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody.

23. 23. The pharmaceutical composition of claim 22, wherein one, two, three or more subcutaneous doses are administered to the patient, the first subcutaneous dose being administered after the last intravenous dose.

24. 24. The pharmaceutical composition of claim 23, wherein the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and subsequent subcutaneous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

25. 25. The pharmaceutical composition of any one of claims 1-24, wherein the patient remains in clinical remission as measured by a GPPGA total score of 0 or 1 for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose.

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