Treatment of asthma with anti-interleukin-33 antibodies

Abstract

The present disclosure relates, inter alia, to methods of treating asthma by administering anti-IL-33 antibodies or antibody variants thereof in specific dosing regimens.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of European Patent Application No. 22192306.3, filed August 26, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to an electronically submitted sequence listing This application incorporates by reference the Sequence Listing submitted with this application in computer readable format (CRF) as a text file entitled "IL33-400-WO-PCT Sequence Listing", created on August 17, 2023, and having a size of 13,496 bytes.

[0003] The present disclosure relates, inter alia, to methods of treating asthma by administering anti-IL-33 antibodies or antibody variants thereof. [Background technology]

[0004] Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and reversible airflow limitation. International guidelines for the treatment of asthma recommend ICS as first-line therapy (GINA 2020). For individuals who are symptomatic on medium-dose ICS monotherapy, step-up therapy with LABA is the recommended next treatment option, followed by other long-term controller medications such as leukotriene receptor antagonists, theophylline, and oral corticosteroids. Biologic agents that inhibit specific molecular targets, such as IgE or Th2 cytokines and their respective receptors (e.g., omalizumab and benralizumab), are reserved for those with severe, uncontrolled asthma. Furthermore, all currently approved long-term controller medications for asthma have little or no effect on the natural history of the disease (i.e., most people with moderate to severe asthma require lifelong therapy). There is a clear unmet need for asthma therapies that not only better control symptoms but also result in disease improvement.

[0005] Numerous studies have demonstrated the critical role of IL-33 in asthma. The genes encoding IL-33 and ST2 / IL1RL1 have been identified as major susceptibility loci for human asthma in several genome-wide association studies (Bonnelykke et al., 2014; Gudbjartsson et al., 2009; Hirota et al., 2011; Moffat et al., 2010; Shrine et al., 2019; Torgerson et al., 2011; Wan et al., 2012). A small number of genes have been reproducibly found to be associated with asthma across diverse ethnic groups. Furthermore, a rare loss-of-function mutation in IL-33 has recently been reported to reduce blood eosinophil counts and protect against asthma (Smith et al., 2017). After adjusting for eosinophil counts, the protective effect remained, albeit attenuated, suggesting that IL-33 may influence asthma risk in part by regulating blood eosinophil counts and through additional biological pathways (Mousas et al., 2017). Two phase II studies support the role of anti-IL-33 therapy in asthma treatment. In a proof-of-concept study involving adult patients with moderate to severe asthma, REGN3500 monotherapy (ICS and LABA maintenance therapy were discontinued during the study) met the primary endpoint of improvement in loss of asthma control and significantly improved lung function compared with placebo, meeting the key secondary endpoint (NCT03387852). In a separate phase II clinical trial, a single IV dose of etoximab was administered to patients with uncontrolled moderate to severe asthma despite treatment with a high-dose ICS and LABA combination. Compared to the placebo group, asthma patients treated with etokimab had a greater improvement in lung function (FEV1) and a decrease in blood eosinophils (NCT03469934).

[0006] Tozolaximab is a human IgG1 mAb that binds to human IL-33. It binds to full-length and mature human IL-33 with very high affinity and prevents IL-33 from binding to soluble (sST2) and membrane-bound ST2 (also known as IL-1RL1) receptors. Several clinical and non-clinical studies have pointed to the IL-33 / ST2 signaling axis as playing an important role in the pathogenesis of asthma.

[0007] This disclosure describes a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of tozorakimab in adult participants with uncontrolled moderate to severe asthma. Summary of the Invention

[0008] The present disclosure provides methods for treating asthma. The methods disclosed herein comprise the administration of an anti-IL-33 antibody or antibody variant thereof.

[0009] The Examples demonstrate that the anti-IL33 antibody tozorakimab (also known as MEDI3506 and 33-670087_7B) may be effective in treating chronic obstructive pulmonary disorder (COPD) and examine the pharmacological activity of tozorakimab with respect to inhibiting IL-33 activity. As outlined in the "Background," at least two clinical trials have demonstrated that IL-33 inhibition may be an effective treatment for asthma. Thus, the tozorakimab dosing regimens disclosed herein that result in effective targeted inhibition in the lung are believed to work well for the treatment of both COPD and asthma.

[0010] In one aspect, the present disclosure provides a method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose of about 300 to about 600 mg at intervals of every four weeks (Q4W) or every eight weeks (Q8W), wherein the anti-IL-33 antibody comprises a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence set forth in SEQ ID NO: 2, and a VHCDR3 having the sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 having the sequence set forth in SEQ ID NO: 5, a VLCDR2 having the sequence set forth in SEQ ID NO: 6, and a VLCDR3 having the sequence set forth in SEQ ID NO: 7.

[0011] In another aspect, the disclosure provides a method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose of about 150 mg at intervals of every four weeks (Q4W), wherein the anti-IL-33 antibody comprises a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 5, a VLCDR2 having the sequence of SEQ ID NO: 6, and a VLCDR3 having the sequence of SEQ ID NO: 7.

[0012] In another aspect, the disclosure provides a method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose effective to achieve at least 80% inhibition of IL-33 in the lung or airway epithelial lining fluid (ELF), wherein the anti-IL-33 antibody comprises a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3, and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 5, a VLCDR2 having the sequence of SEQ ID NO: 6, and a VLCDR3 having the sequence of SEQ ID NO: 7.

[0013] In some cases, the dose is effective to achieve at least about 90%, optionally at least 95%, inhibition of IL-33 in the lung.

[0014] In some cases, the dose is about 300 to about 600 mg at intervals of every 2 weeks (Q2W), every 4 weeks (Q4W), or every 8 weeks (Q8W). In some cases, the dose is about 300 mg Q8W. In some cases, the dose is about 300 mg Q4W. In some cases, the dose is about 150 mg Q4W. In some cases, the dose is about 300 mg Q2W.

[0015] In some cases, the anti-IL-33 antibody or antibody variant thereof is selected from a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0016] In some cases, the anti-IL-33 antibody or antibody variant thereof is an IgG1.

[0017] In some cases, the anti-IL-33 antibody or antibody variant thereof is a human antibody.

[0018] In some cases, the anti-IL-33 antibody or antibody variant thereof comprises a VH domain at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO:4 and a VL domain at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO:8.

[0019] In some cases, the anti-IL-33 antibody comprises a VH domain sequence set forth in SEQ ID NO:4 and a VL domain sequence set forth in SEQ ID NO:8.

[0020] In some cases, the anti-IL-33 antibody comprises a light chain sequence set forth in SEQ ID NO:9 and a heavy chain sequence set forth in SEQ ID NO:10.

[0021] In some cases, the anti-IL-33 antibody variant has the same pharmacokinetic (pK) properties as tozolaximab in humans.

[0022] In some cases, the anti-IL-33 antibody is tozolaximab.

[0023] In some cases, administration is subcutaneous.

[0024] In some instances, for any of the preceding embodiments, the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 12 weeks. In some instances, for any of the preceding embodiments, the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 24 weeks. In some instances, for any of the preceding embodiments, the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 52 weeks. [Brief explanation of the drawings]

[0025] [Figure 1A] 1 shows the amount of IL-33 / tozoraximab complex measured in the serum of healthy participants from Part I of NCT03096795. [Figure 1B] 1 shows the amount of IL-33 / sST2 complex measured in the serum of healthy participants from Part I of NCT03096795. [Figure 1C] 1 shows the amount of IL-33 / tozoraximab complex measured in the serum of participants with COPD from Part II of NCT03096795. [Figure 1D] 1 shows the amount of IL-33 / sST2 complex measured in the serum of participants with COPD from Part II of NCT03096795. [Figure 2A] 1 shows nasal lining fluid levels of free IL-33red plus IL-33red / tozolaximab measured on day 29 in the 300 mg MAD cohort. [Figure 2B] 1 shows nasal lining fluid levels of free IL-33red measured on day 29 in the 300 mg MAD cohort. [Figure 2C] Nasal lining fluid levels of free IL-33ox measured on day 29 in the 300 mg MAD cohort are shown. [Figure 3]1 shows that tozorakimab inhibits an ex vivo IL-33 challenge in whole blood from healthy participants. [Figure 4A] Serum levels of IL-5 on days 1, 14, and 28 in participants in the 300 mg MAD cohort (placebo, n=6; tozorakimab (n=6)). Plots show mean ± SEM. A mixed-effects longitudinal model was used to generate a p-value comparing biomarker trajectories between tozorakimab and placebo (p=0.0037). [Figure 4B] Figure 1 shows serum levels of IL-13 on days 1, 14, and 28 in participants in the 300 mg MAD cohort (placebo, n=6; tozorakimab (n=6). Plots show mean ± SEM. A mixed-effects longitudinal model was used to generate a p-value comparing biomarker trajectories between tozorakimab and placebo (p=0.034). [Figure 4C] Figure 1 shows serum levels of eosinophils on days 1, 14, and 28 in participants in the 300 mg MAD cohort (placebo, n=6; tozorakimab (n=6). Plots show mean ± SEM. A mixed-effects longitudinal model was used to generate a p-value comparing biomarker trajectories between tozorakimab and placebo (p=0.0023). [Figure 5] FIG. 1 shows that Alternaria alternata induces rapid IL-33 release in the bronchoalveolar lavage fluid (BALF) of humanized IL-33 mice. [Figure 6] Figure 1 shows that tozolaximab inhibits ALT-induced BALF IL-5 in humanized IL-33 mice. Test substances were administered intranasally -24 hours before ALT challenge. BALF was collected 24 hours after ALT challenge and analyzed for the presence of IL-5. One-way ANOVA with Bonferroni's multiple comparison test was used to determine significant effects of test substances. ***p<0.001, **p<0.01 (n=4). [Figure 7A]1 shows scratch wound healing in normal human bronchial epithelial cells upon treatment with wild-type IL-33 (IL-33), oxIL-33, and oxIL-33 plus anti-ST2 antibody. [Figure 7B] Quantification of % wound closure from the scratch wound assay described in FIG. 3A is shown. [Figure 8] 1 shows that scratch wound injury was also observed in bronchial epithelial cells obtained from COPD subjects. [Figure 9] Shows the % scratch closure in A549 cells with increasing concentrations of tozolaximab and anti-TSLP antibody. [Figure 10] This is an explanation of the PK / PD target engagement model. [Figure 11] Predicted tozorakimab systemic concentrations are shown relative to observed tozorakimab systemic concentrations from the Ph 1 dose cohort. [Figure 12] 1 shows predicted versus observed tozorakimab:IL-33 complex formation from the Ph1 dose cohort. [Figure 13] Predicted versus observed IL-33:sST2 complex reduction from the Ph1 dose cohort. [Figure 14] Dose response for IL33 / sST2 complex inhibition in blood shows predicted IL-33 inhibition (Q2W - top line; Q4W - middle line; Q6W - bottom line). [Figure 15] Figure 1 shows predicted suppression of IL-33 in the lung at trough by tozorakimab (Q4 W - top line; Q8W - bottom line). [Figure 16] 1 shows predicted tozorakimab serum concentrations after 300 mg Q4W (top line) and 300 mg Q8W (bottom line). The serum concentrations required for 60%, 80%, and 90% identification in the Alternaria mouse model are indicated by dashed lines. [Figure 17] 1 shows predicted tozolaximab serum concentrations after 300 mg Q4W (top line) and 150 mg Q4W (bottom line). The serum concentration threshold for response in the scratch wound closure assay is indicated by the dashed line. [Figure 18] Also shown are predicted tozorakimab systemic concentrations versus observed tozorakimab systemic concentrations from the Ph1 dose cohort. [Figure 19] Also shown are the predicted versus observed IL-33:sST2 complex reductions from the Ph1 dose cohort. DETAILED DESCRIPTION OF THE INVENTION

[0026] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term "about" or "approximately" precedes the first number in a series of two or more numbers, it is understood that the term "about" or "approximately" applies to each of the numbers in the series.

[0027] asthma Asthma is a chronic inflammatory disease of the airways that affects 1-18% of the population in various countries and is characterized by bronchial hyperresponsiveness and reversible airflow limitation. Asthma is defined by a history of respiratory symptoms, including wheezing, dyspnea, chest tightness, and cough. The etiology of asthma is thought to be multifactorial, with recognizable clusters of demographic, clinical, and / or pathophysiological phenotypes. For patients with more severe phenotypes, several phenotype-guided treatments are available. However, a strong relationship between pathological symptoms, clinical manifestations, and response to treatment has not been established.

[0028] Various asthma subtypes have been identified, including allergic asthma, non-allergic asthma, late-onset asthma (which tends to be typically non-allergic), asthma with persistent airflow limitation (associated with airway wall remodeling, resulting in long-term persistent irreversible airflow limitation), and asthma associated with obesity (typically associated with a non- / hypoeosinophilic mechanism of action).

[0029] There are various levels of asthma severity, which are currently assessed retrospectively based on the level of treatment required to control symptoms and exacerbations. The severity index includes three major groups: mild asthma, moderate asthma, and severe asthma. Asthma severity is defined on the GINA scale by the level of treatment required to achieve adequate symptom control. The GINA scale is defined in the "Pocket Guide for Asthma Management and Prevention," Global Initiative for Asthma; 2019.

[0030] In certain instances, subjects suitable for treatment with the methods disclosed herein suffer from moderate asthma, severe asthma, or moderate to severe asthma. In some cases, subjects suitable for treatment with the methods disclosed herein have asthma that is not adequately controlled with standard of care controller or reliever medications as defined by steps 1 and 2 of the GINA scale.

[0031] In certain instances, subjects suitable for treatment with the methods disclosed herein suffer from moderate asthma uncontrolled by standard of care, severe asthma uncontrolled by standard of care, and moderate-to-severe asthma uncontrolled by standard of care (SOC) as defined by the GINA scale.

[0032] Asthma can be diagnosed or assessed by several different measures, including: Airway inflammation was assessed using standardized tidal partial pressure of exhaled nitric oxide (FeNO) (ATS, Am J Repir Crit Care Med. 171(8):912-30, 2005). Although FeNO has not been established to confirm the diagnosis of asthma, elevated FeNO has been associated with asthma characterized by type 2 airway inflammation.

[0033] Determination of atopic status. This can be identified by skin prick testing using common environmental allergies or by measuring the level of specific IgE in serum. As with FeNO, allergy testing does not confirm or exclude the diagnosis of asthma, but the presence of atopy increases the likelihood that a patient with respiratory symptoms has allergic asthma.

[0034] Bronchial provocation tests. These tests assess airway hyperresponsiveness (AHR) by monitoring variable airflow limitation. Subjects can be challenged with chemical agents such as methacholine. Such tests are moderately sensitive for diagnosing asthma.

[0035] The Asthma Control Questionnaire (ACQ)-6 is a patient-reported questionnaire that assesses asthma symptoms (i.e., nighttime awakenings, awakening symptoms, activity limitations, shortness of breath, and wheezing) as well as daily rescue bronchodilator use and FEV1 (Juniper et al., October 1999). The ACQ-6 is a shortened version of the ACQ, omitting the FEV1 measurement from the original ACQ score. Questions are equally weighted and scored from 0 (completely controlled) to 6 (severely uncontrolled). The mean ACQ score is the average of the responses. A mean score of 0.75 indicates well-controlled asthma, a score between 0.75 and 1.5 indicates partially controlled asthma, and a score above 1.5 indicates uncontrolled asthma (Juniper et al., Respir Med. 1 00(4):616-21, 2006). An individual change of at least 0.5 is considered clinically meaningful (Juniper et al., Respir Med. 99(5):553-8, 2005). In certain examples, patients suitable for treatment with the methods contemplated herein have an ACQ-6 score of 1.5 or greater prior to the first dose of a treatment contemplated herein.

[0036] Spirometry is performed in accordance with the ATS / European Respiratory Society (ERS) guidelines (Miller et al., Eur Respir J. 26(1):153-61, 2005). For example, multiple forced expiratory efforts (at least three but no more than eight) are performed in each spirometry session, and two maximal efforts that meet the ATS / ERS acceptability and reproducibility criteria are recorded. Maximal efforts are based on the highest FEV1. The maximum fluvial expiratory volume (FEV1) of the two maximal efforts is used for analysis. Both absolute measurements (for FEV1 and forced vital capacity (FVC)) and percentages of predicted normal values ​​are recorded using appropriate reference values. Maximum FVC is reported regardless of the effort at which it occurred (even if the effort did not result in a maximum FEV1). In certain examples, patients suitable for treatment with the methods contemplated herein have a morning pre-BD FEV1 of 40% or greater than predicted normal and greater than 1 L, but a pre-BD FEV1 of less than 85% of predicted normal.

[0037] Post-bronchodilator (post-BD) spirometry testing is assessed after subjects undergo pre-BD spirometry. Maximal bronchodilation is induced using a short-acting beta-agonist (SABA), such as albuterol (90 1-1 g metered dose) or salbutamol (100 1-1 g metered dose) or equivalent, with a spacer device for a total of up to eight inhalations (Sorkness et al., J Appl Physiol. 1 04(2):394-403, 2008). Reversibility is determined and analyzed using the maximum pre-BD FEV1 and post-BD FEV1 obtained after four, six, or eight inhalations. The reversibility algorithm is as follows: Reversibility %=(FEV1 after BD-FEV1 before BD)×100 / FEV1 before BD

[0038] In certain examples, patients suitable for treatment with the methods contemplated herein have a % reversibility of 12% or greater and 200 mL or greater (e.g., 15-60 minutes after 4 inhalations of albuterol / salbutamol).

[0039] In some cases, subjects suitable for treatment with the methods disclosed herein have been diagnosed with early-onset asthma. As defined herein, "early-onset" asthma refers to subjects diagnosed with asthma before the age of 25, preferably before the age of 18. Diagnosis can be made by a clinician, for example, using any one of several well-known methods for diagnosing asthma. It should be understood that the methods disclosed herein for use in patients with early-onset asthma are not limited to subjects under the age of 25 (or even under the age of 18). For example, the methods can be used on adults (defined herein as those over the age of 18) who have suffered from asthma since before the age of 25.

[0040] Dosing regimen The present disclosure relates to a dosing regimen for an anti-IL-33 antibody or antibody variant that finds particular efficacy in the treatment of asthma. The dosing regimen consists of one or more controlled-sized doses administered throughout the treatment period. When multiple doses are present, the doses are separated by a dosing interval. The anti-IL-33 antibody or antibody variant is administered in a therapeutically effective amount. As used herein, an "effective amount" or "therapeutically effective amount" of an agent, e.g., a pharmaceutical formulation comprising an IL-33 antibody, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0041] The dose size of an anti-IL-33 antibody or antibody variant thereof can be expressed as the weight of the anti-IL-33 antibody or antibody variant thereof. In certain cases, the anti-IL-33 antibody or antibody variant thereof is administered at a dose of about 400 to about 800 mg, about 450 to about 750 mg, about 500 to about 700 mg, about 510 to about 690 mg, about 520 to about 680 mg, about 530 to about 670 mg, about 540 to about 660 mg, about 550 to about 650 mg, about 560 to about 640 mg, about 570 to about 630 mg, about 580 to about 620 mg, about 590 to about 630 mg, or about 600 mg.

[0042] In some cases, the dose is 600 mg. In some cases, the anti-IL-33 antibody or antibody variant thereof is formulated for subcutaneous injection at 150 mg / mL, such that the 600 mg dose is administered as a 4 mL treatment. A 600 mg dose of the anti-IL-33 antibody or antibody variant thereof may be administered as two simultaneous 300 mg doses. As used herein, "simultaneous" doses refer to doses administered at the same time or sequentially administered doses separated by no or only a minimal amount of time (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0043] In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at a dose of about 200 to about 400 mg, about 250 to about 350 mg, about 260 to about 340 mg, about 270 to about 330 mg, about 280 to about 320 mg, about 290 to about 310 mg, about 295 to about 305 mg, or about 300 mg.

[0044] In some cases, the dose is 300 mg. In some cases, the anti-IL-33 antibody or antibody variant thereof is formulated for subcutaneous injection at 150 mg / mL, such that the 300 mg dose is administered as a 2 mL treatment. In some cases, a 300 mg dose of the anti-IL-33 antibody or antibody variant thereof may be administered as two simultaneous 150 mg doses. As used herein, "simultaneous" doses refer to doses administered at the same time or sequentially administered doses separated by no or only a minimal amount of time (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0045] In some cases, the dose is 150 mg. In some cases, the anti-IL-33 antibody or antibody variant thereof is formulated for subcutaneous injection at 150 mg / mL, such that a 150 mg dose is administered as a 1 mL treatment.

[0046] The dose size of an anti-IL-33 antibody or antibody variant thereof can be expressed in terms of the plasma drug concentration provided by the dose, as an amount of active compound engineered to provide a constant level of plasma drug concentration. By varying the amount, bioavailability, or timing / frequency of administration of the antibody or variant, one skilled in the art can control the plasma concentration in a subject. Because plasma concentrations vary over time with drug uptake and clearance, they can be expressed in various standardized ways, such as as a maximum, minimum (trough), or over time.

[0047] In some cases, the dose is selected to provide a Cmax,ss (maximum observed concentration at steady state) of about 20 to about 50 μg / mL, about 25 to about 45 μg / mL, about 30 to about 40 μg / mL, about 35 to about 40 μg / mL, or about 37 μg / mL. maz.ss is observed during the dosing period. In this context, "dosing period" refers to the time between two consecutive doses.

[0048] The Examples show that a 300 mg Q4W or Q8W dosing regimen of MEDI3506 achieves the serum concentrations required for inhibition of both the redIL-33:ST2 signaling axis and the oxIL-33:RAGE / EGFR signaling axis, and is predicted to achieve sustained dual pathway inhibition (Figures 16 and 17). MEDI3506 serum concentrations can be measured using anti-drug antibody reagents in an assay format suitable for capturing and detecting MEDI3506 from biological samples (e.g., blood) (hence, C). max.ss (used to determine MEDI3506). In some cases, the assay may use an anti-IgG1 capture mAb and a stabilized MEDI3506 antigen labeled with a detectable marker. The detectable marker can be quantified to determine the concentration of MEDI3506. In some cases, the MEDI3506 antigen (IL-33) can be stabilized in a reduced form by, for example, mutating one or more cysteine ​​residues to serine to prevent conversion of redIL-33 to an oxidized form (oxIL-33) via disulfide bond formation. Assays and platforms suitable for detecting serum biomarkers are well known to those of skill in the art.

[0049] In some cases, the dose is selected to provide a Cmax,ss of about 10 to about 35 μg / mL, about 15 to about 30 μg / mL, about 15 to about 30 μg / mL, about 15 to about 25 μg / mL, about 15 to about 20 μg / mL, or about 18.6 μg / mL.

[0050] In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at a dose selected to provide an area under the plasma concentration-time curve (AUC) throughout the administration period.

[0051] In some cases, the dose is selected to provide an AUC of about 400 to about 800 μg·day / mL, about 500 to about 750 μg·day / mL, about 600 to about 700 μg·day / mL, about 600 to about 650 μg·day / mL, about 600 to about 620 μg·day / mL, about 610 to about 620 μg·day / mL, or about 616 μg·day / mL over the administration period.

[0052] In some cases, the dose is selected to provide an AUC of about 200 to about 515 μg·day / mL, about 250 to about 500 μg·day / mL, about 300 to about 450 μg·day / mL, about 300 to about 350 μg·day / mL, or about 323 μg·day / mL over the administration period.

[0053] In some cases, the dose is selected to provide an AUC of about 100 to about 300 μg·day / mL, about 100 to about 250 μg·day / mL, about 100 to about 200 μg·day / mL, about 150 to about 200 μg·day / mL, or about 161.5 μg·day / mL over the administration period.

[0054] Administration of the anti-IL-33 antibody or antibody variant thereof is carried out as multiple doses separated by a dosing interval. In some cases, the dosing interval is 2 weeks (14 days), 3 weeks (21 days), 4 weeks (28 days), or 5 weeks (35 days). In some embodiments, the dosing interval is 4 weeks (28 days). In some cases, the dosing interval is about 4 weeks (i.e., 28±4 days). In some cases, the dosing interval is about 8 weeks (i.e., 56±4 days).

[0055] In some cases, a dose may be administered over multiple days, for example, as two or more separate doses. As used herein, a "split dose" refers to a divided dose of a therapeutic agent, such that the total amount of the therapeutic agent administered in the split doses equals the total dose. Any split amount may be used, for example, two, three, four, five, or more split doses may comprise a single dose. In some cases, a dose may be administered as two or more split doses separated by a period of one, two, three, four, five, or six days. In some cases, a dose may be administered as two or more split doses separated by a period of one, two, or three weeks. The split doses may be administered on two, three, four, or more consecutive days. The split doses comprising a dose may be of equal size or different sizes, as long as their sum equals the dose.

[0056] Thus, as used herein, a 600 mg dose having a 4-week administration period (Q4W) may be replaced by 150 mg administered weekly (Q1W), 300 mg administered every two weeks (Q2W), or 450 mg administered every three weeks (Q3W), all of which provide a dosing regimen equivalent to 600 mg every four weeks. Thus, in some cases, the dose is approximately 300 mg Q2W. A 300 mg dose having a 4-week administration period (Q4W) may be replaced by 150 mg administered every two weeks (Q2W) or 75 mg administered every week (Q1W). A 300 mg dose having an 8-week administration period (Q8W) may be replaced by 150 mg administered every four weeks (Q4W), 75 mg administered every two weeks (Q2W), or 37.5 mg administered every week (Q1W).

[0057] When expressing the dosing interval in weeks, a margin of error is allowed, such that one week can be expressed as 7 days ± 1 day. In some embodiments, one week can be expressed as 7 days ± 0.5 days, 7 days ± 0.25 days, or exactly 7 days. When the dosing interval is multiple weeks, the margin of error for each week can be combined. For example, in some cases, the dosing interval is 4 weeks ± 4 days. In some cases, the dosing interval is 4 weeks ± 3 days. In some embodiments, the dosing interval is 4 weeks ± 2 days. In some embodiments, the dosing interval is 4 weeks ± 1 day. In some cases, the dosing interval is exactly 4 weeks. In some cases, the dosing interval is 8 weeks ± 4 days. In some cases, the dosing interval is 8 weeks ± 3 days. In some cases, the dosing interval is 8 weeks ± 2 days. In some cases, the dosing interval is 8 weeks ± 1 day. In some cases, the dosing interval is exactly 8 weeks.

[0058] In some cases, the anti-IL-33 antibody or antibody variant thereof is administered during a "treatment window" (which, as used herein, refers to the period beginning with the first administration of the anti-IL-33 antibody or antibody variant thereof and continuing through the final administration). The day of the first administration is referred to as "day 1" of "week 0," with week 1 beginning 7 days later, week 2 beginning 7 days after that, and so on. In some embodiments, the treatment window is 12 weeks long (i.e., spanning weeks 0 through 12). In some embodiments, the treatment window is 16 weeks long (i.e., administered from week 0 through week 15), with the dosing interval being 4 weeks, such that a total of four administrations are administered (at weeks 0, 4, 8, and 12, respectively). In some embodiments, the treatment period is 12 weeks long, with administration occurring 4 weeks apart, such that administration occurs on day 1 (week 0), day 29±4 (week 4), day 57±4 (week 8), and day 85±4 (week 12).

[0059] In some cases, the treatment period is 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, 52 weeks, or more. In some cases, the treatment period is 52 weeks or more. In some cases, the treatment period is 48 weeks or more.

[0060] In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at approximately 300 mg Q4W. This example shows that administration of MEDI3506 300 mg Q4W is predicted to achieve approximately 94% depletion (target engagement) in the lungs. This level of target engagement is potentially greater than that predicted to be achieved for the anti-IL-33 antibody itepekimab, whose recent Phase II study in COPD resulted in a significant reduction in COPD exacerbations and a significant improvement in FEV1 in former smokers (Rabe et al., 2021). Itepekimab has a reportedly significantly longer half-life compared to MEDI3506 (SAR440340 and the t value of itepekimab, also known as REGN3500). 1 / 2 (U.S. Patent Application Publication No. 2021 / 0000949 reports a 30-day response rate of 100mg / kg (see paragraph

[0411] therein).) Such administration is also suitable for treating asthma, as depletion is desirable in treating both conditions.

[0061] In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at about 300 mg Q8W. The Examples show that administration of MEDI3506 at 300 mg Q8W (i.e., with a dosing period twice as long) is predicted to result in approximately 83% inhibition of IL-33 at trough in lung tissue, and thus may provide sufficient efficacy in asthma at a more convenient dosing frequency for patients compared to Q4W.

[0062] Thus, in some cases, the IL-33 antibody or antibody variant thereof is administered at a dose that achieves at least 80%, 85%, or 90% target engagement in the lung. In some cases, the dose achieves at least 90% target engagement in the lung. In some cases, the dose achieves at least 91%, 92%, 93%, or 94% target engagement in the lung. In some cases, the % target engagement is achieved at trough concentrations.

[0063] Anti-IL-33 antibody The treatments described herein relate to anti-IL-33 antibodies, and variants and fragments thereof.

[0064] Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family, encoded by the IL33 gene. IL-33 is constitutively expressed in multiple cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. IL-33 expression has also been reported to be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress caused by environmental triggers, such as allergens, toxins, and pathogens, as well as mechanical injury, can lead to IL-33 release. Free IL-33 associates with the heterodimeric IL-33 receptor complex, which is composed of the suppressor of tumorigenicity 2 (ST2) protein and the interleukin-1 receptor accessory protein (IL-1 RAcP), and activates the AP-1 and NF-κB pathways via the adaptor proteins myeloid differentiation primary response 88 (MyD88) and possibly the MyD88 adaptor-like (Mal) protein. IL-33 stimulates multiple cell types, including innate lymphoid type II cells (ILC2s), mast cells, basophils, eosinophils, and dendritic cells, to promote immune responses.

[0065] The terms "interleukin-1 receptor-like 1 (IL1RL1)" and "ST2," used interchangeably herein, refer to any native ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. ST2 is also referred to in the art as DER4, T1, and FIT-1. The term encompasses "full-length," unprocessed ST2, as well as any form of ST2 resulting from intracellular processing. At least four isoforms of ST2 are known in the art, including soluble (sST2, also known as IL1RL1-a) and transmembrane (ST2L, also known as IL1RL1-b) forms resulting from differential mRNA expression from a dual promoter system, and ST2V and ST2LV forms resulting from alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor (TIR) ​​domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and contains a unique nine-amino acid (aa) C-terminal sequence (see, e.g., Kakkar et al., Nat. Rev. Drug Disc. 40 7:827-840, 2008). sST2 can function as a decoy receptor to inhibit soluble IL-33. The term also encompasses naturally occurring variants of ST2, such as splice variants (e.g., ST2V, which lacks the third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic polymorphisms (e.g., variants that are protective against or confer asthma risk as described herein). An exemplary amino acid sequence of human ST2 can be found, for example, at UniProtKB Accession No. 001638. ST2 is part of the IL-33 receptor together with the co-receptor protein IL-1 RAcP.Binding of IL-33 to ST2 and the co-receptor interleukin-1 receptor accessory protein (IL-1 RAcP) forms a 1:1:1 ternary signaling complex to promote downstream signaling (Lingel et al., Structure 17(10):1398-1410, 2009, and Liu et al., Proc. Nat. Acad. Sci. 11 0(37):14918-14924, 2013).

[0066] It is believed that antibodies or antibody variants that specifically bind to and inhibit components of the IL-33 / ST2 signaling axis may be useful in the treatment of asthma.

[0067] "Antibody" is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0068] Anti-IL33 antibodies or antibody variants, i.e., antibodies that specifically bind to and inhibit / neutralize IL-33, are particularly believed to be effective in treating asthma. In some cases, the antibodies may be monoclonal (MAb); recombinant; chimeric; humanized, e.g., complementarity-determining region (CDR)-grafted; human; antibody variants, including single-chain; and / or bispecific; as well as fragments; variants; or derivatives thereof. Antibody fragments include portions of antibodies that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments generated by enzymatic cleavage of full-length antibodies. Other binding fragments include those generated by recombinant DNA techniques, such as expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.

[0069] Monoclonal antibodies can be engineered for use as therapeutic or diagnostic agents. As used herein, "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides, including antibodies, bispecific antibodies, etc., having substantially identical amino acid sequences or derived from the same genetic source. The term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0070] One example is a "chimeric" antibody in which a portion of the heavy (H) and / or light (L) chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, so long as they exhibit the desired biological activity. See U.S. Pat. No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0071] In another example, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. Humanization can be accomplished, for example, by substituting at least a portion of a rodent complementarity-determining region for the corresponding region of a human antibody, using methods described in the art (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36).

[0072] Also contemplated are human antibodies and antibody variants (including antibody fragments) that bind to IL-33. Using transgenic animals (e.g., mice) capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production, such antibodies are produced by immunization with a polypeptide antigen (i.e., having at least six consecutive amino acids), optionally conjugated to a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in Immuno. 7:33. See also PCT Application Nos. PCT / US96 / 05928 and PCT / US93 / 06926. Further methods are described in U.S. Patent No. 5,545,807, PCT Application Nos. PCT / US91 / 245 and PCT / GB89 / 01207, and European Patent Nos. 54607381 and 546073(A1). Human antibodies may also be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells, as described herein.

[0073] Chimeric, CDR-grafted, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. Nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In one example, the antibody is produced in a mammalian host cell, such as a CHO cell. Monoclonal (e.g., human) antibodies can be produced by expression of recombinant DNA in a host cell or by expression in a hybridoma cell, as described herein.

[0074] Antibodies and antibody variants (including antibody fragments) useful in the present methods may comprise (a) a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 5, a VLCDR2 having the sequence of SEQ ID NO: 6, and a VLCDR3 having the sequence of SEQ ID NO: 7.

[0075] Also contemplated for use in the methods disclosed herein are anti-IL-33 antibodies or antibody variants thereof comprising a heavy chain variable region (VH) domain at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO: 4. In some cases, the anti-IL-33 antibody or antibody variant thereof comprises a light chain variable region (VL) domain at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO: 8. In some cases, the anti-IL-33 antibody or antibody variant thereof comprises (a) a heavy chain variable region (VH) at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO: 4, and (b) a light chain variable region (VL) at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO: 8.

[0076] In some cases, the anti-IL-33 antibody is 33_640087_7B, as disclosed in WO 2016 / 156440, which is incorporated herein by reference. 33_640087_7B, also known in the art as MEDI3506 and tozolaximab, is an anti-IL-33 antibody that binds with high affinity to the reduced form of IL-33 (redIL-33). 33_640087_7B also inhibits the conversion of redIL-33 to the oxidized form (oxIL-33), which has been shown to induce RAGE-mediated signaling and induce epithelial cell proliferation.

[0077] 33_640087_7B is an exemplary anti-IL-33 antibody having (a) a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3, and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 5, a VLCDR2 having the sequence of SEQ ID NO: 6, and a VLCDR3 having the sequence of SEQ ID NO: 7.

[0078] 33_640087_7B also comprises a VH domain having the amino acid sequence set forth in SEQ ID NO:4 and a VL domain having the amino acid sequence set forth in SEQ ID NO:8.

[0079] 33_640087_7B is an IgG1 antibody, and the full-length light and heavy chain sequences of 33_640087_7B, including the IgG1 chain, are shown in SEQ ID NOs: 9 and 10, respectively.

[0080] In some cases, the anti-IL-33 antibody or antibody variant thereof has similar or the same pharmacokinetic (pK) properties as 33_670087_7B in humans.

[0081] In particular, an anti-IL-33 antibody or antibody variant may have a half-life in humans similar to or the same as that of 33_670087_7B. An anti-IL-33 antibody or antibody variant having a half-life similar to or the same as that of 33_670087_7B in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 12.7 days when administered at a dose of 30 mg Q2W. An anti-IL-33 antibody or antibody variant having a half-life similar to or the same as that of 33_670087_7B in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 13.2 days when administered at a dose of 100 mg Q2W. An anti-IL-33 antibody or antibody variant with a similar or identical half-life in humans to 33_670087_7B may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days when administered at a dose of 300 mg Q2W.

[0082] In some cases, an IL-33 antibody or variant thereof may competitively inhibit the binding of IL-33 to 33_640087-7B (as described in WO 2016 / 156440). WO 2016 / 156440 discloses that 33_640087-7B binds to redIL-33 with particularly high affinity and attenuates both ST-2- and RAGE-dependent IL-33 signaling. An antibody or variant thereof is said to competitively inhibit the binding of a reference antibody to a given epitope if it specifically binds to that epitope to the extent that it blocks, to some extent, the binding of the reference antibody to that epitope. Competitive inhibition can be determined by any method known in the art, for example, by solid-phase assays such as competitive ELISA assays, dissociation-promoted lanthanide fluorescence immunoassays (DELFIA®, Perkin Elmer), and radioligand binding assays. For example, one skilled in the art can determine whether an antibody or its variant competes for binding to IL-33 by using an in vitro competitive binding assay (e.g., the HTRF assay described in paragraphs 881-886 of WO 2016 / 156440, incorporated herein by reference). For example, one skilled in the art can label 33_640087-7B with a donor fluorophore and mix multiple concentrations with a fixed concentration sample of acceptor fluorophore-labeled redIL-33. Subsequently, fluorescence resonance energy transfer between the donor fluorophore and acceptor fluorophore in each sample can be measured to confirm binding characteristics. To identify competitively binding antibody molecules, one skilled in the art can first mix various concentrations of a test binding molecule with a fixed concentration of labeled 33_640087-7B antibody. A decrease in FRET signal when the mixture is incubated with labeled IL-33 compared to a positive control of labeled antibody alone indicates competitive binding to IL-33. An antibody or variant thereof can be said to competitively inhibit the binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0083] In various examples, the anti-IL-33 antibody or antibody variant thereof is selected from a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. In some cases, the anti-IL-33 antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, a single domain antibody, and an scFv, wherein the dose is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody.

[0084] In some cases, the anti-IL-33 antibody or antibody variant thereof binds to IL-33 comprising the amino acid sequence of SEQ ID NO: 11. In various cases, the anti-IL-33 antibody or antibody variant thereof may be capable of binding to a mature form of the full-length IL-33 protein comprising the amino acid sequence of SEQ ID NO: 11. In various cases, the anti-IL-33 antibody or antibody variant thereof may be capable of binding to an IL-33 protein fragment comprising amino acids 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, or 112-270 of SEQ ID NO: 11.

[0085] In various cases, an anti-IL-33 antibody or antibody variant thereof may be capable of binding to the reduced form (red-IL-33) and / or the oxidized form (ox-IL-33) of IL-33. In some cases, an anti-IL-33 antibody or antibody variant thereof may be capable of preferentially binding to the reduced form (red-IL-33) and / or the oxidized form (ox-IL-33) of IL-33.

[0086] In various cases, the anti-IL-33 antibody or antibody variant thereof may be an inhibitory antibody capable of inhibiting IL-33 or a fragment thereof as defined herein. In various cases, the inhibitory antibody may be capable of inhibiting the association of IL-33 or a fragment thereof with the IL-33 receptor. [Example]

[0087] Example 1 - Demonstration of the mechanism of action of the anti-interleukin-33 antibody tozolaximab: Results of a Phase 1 study in healthy adults and participants with chronic obstructive pulmonary disease The alarmin cytokine interleukin (IL)-33 orchestrates inflammatory and remodeling responses after tissue injury (Scott IC et al., Sci Rep 2018;8:3363; Cohen E et al., Nat Commun 2015;6:8327; Murdaca G et al., Int J Mol Sci 2019;20:5856). Excess IL-33 plays a key role in the development and progression of chronic obstructive pulmonary disease (COPD) (Allinne J et al., J Allergy Clin Immunol 2019;144:1624-37.e10; Schmitz J et al., Immunity 2005;23:479-90). Tozolaximab (MEDI3506) is a human immunoglobulin G1 monoclonal antibody that specifically and potently targets IL-33. This first-in-human trial (NCT03096795) evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of tozorakimab. This report details the demonstration of tozorakimab's mechanism of action from this study.

[0088] method This three-part, phase 1, randomized, blinded, placebo-controlled trial was conducted at two centers in the UK from May 15, 2017, to September 30, 2019. In all cohorts, participants were randomized 3:1 to receive tozorakimab:placebo. This report presents data from parts 1 and 2.

[0089] In Part 1, eligible participants with a history of mild atopy and sensitivity to house dust mites (HDM) received a single ascending dose (SAD) of 300 mg intravenously (IV) or 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, or 300 mg subcutaneously (SC) of either tozolaximab or placebo. In Part 2, eligible participants with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade I-II COPD received multiple ascending doses (MAD) of 30 mg, 100 mg, or 300 mg SC tozolaximab or placebo.

[0090] Pharmacodynamics (PD) was evaluated as an exploratory endpoint. Target engagement was measured using a superselective assay for IL-33 forms in serum (all cohorts) and in local airway nasal lining fluid (MLF) samples by noninvasive nasal adsorption (MAD cohort). Serum levels of sST2 were also measured. After IL-33 challenge, interferon gamma (IFN-γ) was measured ex vivo using a whole blood assay (SAD cohort). The PD effects of tozolaximab on inflammatory mediators were investigated (MAD cohort) using a multiplex immunoassay (Meso Scale Discovery). Eosinophil levels were measured in whole blood (MAD cohort).

[0091] result Patient baseline demographics were as follows:

[0092] [Table 1]

[0093] A total of 56 participants were enrolled and randomized to the SAD cohort (healthy adults with mild atopy and susceptibility to HDM): 42 to receive tozorakimab and 14 to receive placebo. Twenty-four patients were enrolled and randomized to the MAD cohort (adults with GOLD grade I-II COPD): 18 to receive tozorakimab and 6 to receive placebo.

[0094] Target engagement biomarker research (exploratory endpoints) Target engagement of tozoraximab was demonstrated in serum (Figure 1) and local airway nasal MLF (Figure 2). In serum, tozoraximab increased IL-33 / tozoraximab complex levels compared to placebo across all cohorts (Figure 1A [SAD cohort] and Figure 1C [MAD cohort]), whereas endogenous IL-33 / sST2 complex levels were reduced across all cohorts (Figure 1B [SAD cohort] and Figure 1D [MAD cohort]). Tozoraximab did not significantly affect serum levels of total sST2 compared to placebo at any dose level.

[0095] In local airway nasal lining fluid (MLF), tozolaximab increased the levels of IL-33 / tozolaximab complexes compared to placebo (MAD cohort) (Figure 2A) and reduced the levels of both reduced and oxidized forms of IL-33 (Figures 2B and 2C).

[0096] Increased levels of tozolaximab in the circulation correlate with decreased levels of induced IFN-γ (lover) (Figure 3).

[0097] Pharmacodynamic biomarker research (exploratory endpoints) Tozolaximab (300 mg SC) significantly reduced serum IL-5 and IL-13 levels compared with placebo (Figures 4A and 4B). Furthermore, tozolaximab significantly reduced blood eosinophil levels (Figure 4C). These reductions correlated with decreases in serum levels of IL-5 (repeated measures correlation [r] = 0.64; 95% confidence interval [CI]: 0.23–0.86, p = 0.0034) and IL-13 (r = 0.75; 95% CI: 0.43–0.91, p = 0.00019).

[0098] conclusion These data demonstrate tozorakimab's mechanism of action through target engagement and identification of PD biomarkers in a first-in-human study in patients with COPD (NCT03096795). Using pioneering nasal suction sampling, we demonstrated target engagement in the circulation and locally in the airways. These results support the entry of tozorakimab into Phase 2 and 3 clinical trials. Phase 2 trials (NCT04631016) and Phase 3 trials (NCT05166889 and NCT05158387) are currently underway to investigate the safety and efficacy of tozorakimab for the treatment of COPD.

[0099] Example 2 - A Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of MEDI3506 in Participants with Moderate to Severe Chronic Obstructive Pulmonary Disease and Chronic Bronchitis (FRONTIER 4) This example describes a phase 2, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 in adult subjects with moderate to severe COPD receiving standard of care (dual or triple therapy) as maintenance therapy. Participants were also receiving stable background therapy but had a history of at least one moderate or severe acute exacerbation in the past 12 months and moderate to severe chronic bronchitis with active sputum production and cough.

[0100] MEDI3506 (also referred to herein as 33_640087_7B) is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds to full-length and mature human IL-33 with very high affinity and prevents IL-33 from binding to the soluble (sST2) and membrane-bound ST2 (also known as IL-1RL1) receptor.

[0101] Several clinical and non-clinical studies have pointed to the IL-33 / ST2 signaling axis as playing an important role in the pathogenesis of COPD, and therefore, blocking this signaling pathway may be therapeutically beneficial in COPD.

[0102] Participants must have been receiving dual therapy (ICS+LABA or LABA+LAMA) or triple therapy (ICS+LABA+LAMA) continuously for at least 3 months prior to enrollment and must continue to do so throughout the study. There must be no change in maintenance COPD treatment after a previous exacerbation prior to study entry.

[0103] Participants were randomized in an overall 1:1 ratio to treatment groups receiving 600 mg of MEDI3506 SC (20 mM L-histidine / L-histidine-hydrochloride, 220 mM L-arginine-hydrochloride, 0.03% (w / v) polysorbate 80, pH 5.5) or volume-matched placebo SC (collectively referred to as "study drug") every 4 weeks (Q4W) for a total of 7 doses, with the final dose at Week 24.

[0104] Participants will be enrolled in this trial over a minimum 4-week screening / run-in period, a 24-week intervention period (or "treatment period") during which they will receive seven SC Q4W doses, a 4-week add-on period, and an 8-week follow-up period. The trial schema is shown in Table 2.

[0105] The primary statistical estimand is as follows: Estimate the mean change from baseline in FEV1 (MEDI 3506-placebo) at week 12 using a repeated measures mixed-effects analysis of covariance model for the intention-to-treat population. This includes all available data from all visits up to and including week 12, regardless of whether participants discontinued the study intervention or received anticonvulsant medication. The model includes fixed effects for baseline, eosinophil stratum, background medication stratum, visit, study intervention, and baseline by visit, as well as study intervention by visit interactions. An unstructured covariance matrix will be used to describe the correlation between participant observations across visits.

[0106] A similar approach will be taken for the analysis of cough VAS, BCSS, CASA-Q, SGRQ, and acute medication treatment. Data may be log-transformed prior to analysis, if necessary. Changes from baseline in objective cough parameters and oscillometric parameters at week 12 will be analyzed using analysis of covariance. Analyses of time-to-event and annualized incidence of event data will include available data for all participants (through week 28, if available). Time-to-event endpoints will be analyzed.

[0107] Screening Procedure Participants must meet the following criteria: 1. Participants must be between 40 and 75 years old. 2. Participants who are current or former smokers with a smoking history of 10 pack-years or more. 3. Participants receive pneumococcal and influenza vaccines on schedule according to local treatment guidelines. 4. Participants with a documented history of COPD for at least 1 year. 5. Participants with post-BD FEV1 / FVC < 0.70 and post-BD FEV1 > 30% but < 80% predicted normal at screening. Central spirometry will be used for this baseline assessment. 6.Participants with a physician-confirmed medical history of chronic bronchitis, defined as the presence of cough and sputum nearly every day for at least 3 months / year for at least 2 years immediately prior to SV1 (screening). 7. Participants with a mean BCSS score of ≥2 in the cough domain and ≥2 in the sputum domain assessed over the 14 days prior to SV3. 8. Participants with a documented stable regimen of dual or triple therapy for ≥ 3 months prior to enrollment, with no change in therapy after a previous exacerbation prior to study entry. Dual therapy consists of ICS + LABA or LABA + LAMA, and triple therapy consists of ICS + LABA + LAMA. Both dual and triple therapy may be in the form of separate fixed-dose combination inhalers, but do not have to be in nebulized form. 9. Participants with a documented history of one or more episodes of moderate or severe AECOPD (or one injection of a depot drug) requiring systemic corticosteroids and / or antibiotics for a period of at least 3 days, or a history of hospitalization for AECOPD within the past 12 months prior to screening. 10. Participants are clinically stable and have no COPD exacerbations for 1 month prior to SV1 (screening) and before Day 1. Body mass index within the range of 11.19 kg / m² or more and 35 kg / m² or less.

[0108] Randomization and Dosing Randomization will occur at Study Visit 3 (Day SV3-1). Participants who continue to meet the eligibility criteria will be randomized to treatment groups as described above. Blood samples, urine samples, efficacy assessments, and safety assessments will be performed to establish a baseline.

[0109] Randomization will be stratified by baseline blood eosinophils (<300 cells / μL vs. ≥300 cells / μL) and background therapy (ICS vs. no ICS).

[0110] The first IP administration will occur at Study Visit 3 (Day 1) and will comprise the first dose of study drug during the treatment period. Administration of 600 mg of MEDI3506 will require 2 x 2 mL SC injections per dose. The placebo group will receive a matching injection volume for the MEDI3506 group.

[0111] At Study Visit 4 (Day 2), participants return for assessment of compliance with self-assessment efficacy reporting procedures and safety assessments. Procedures are outlined in Table 4.

[0112] The second study drug dose will occur at Study Visit 6 (Day 29 ± 3).

[0113] The third study drug administration will occur at Study Visit 7 (Day 57 ± 3).

[0114] The fourth study drug administration will occur at Study Visit 8 (Day 85 ± 3).

[0115] The fifth study drug administration will occur at Study Visit 9 (Day 113 ± 3).

[0116] The sixth study drug administration will occur at Study Visit 10 (Day 141 ± 3).

[0117] The seventh and final study drug administration will occur at Study Visit 11 (Day 169±3).

[0118] endpoint The primary endpoint visit will occur at Week 12, as assessed at Study Visit 10 (Day 113±4).

[0119] The primary endpoint was improvement in pre-clinical BD FEV1, which is the change from baseline to week 12. Forced expiratory volume in 1 second is a validated clinically important endpoint in COPD trials and is widely used in trials used to support enrollment of add-on treatments to the current standard of care (double / triple therapy) in similar chronic bronchitis patient populations (Martinez et al., 2015).

[0120] Based on available data, the improvement in FEV1 estimated in the sample size determination is expected to be achieved by week 12. However, while the improvement in FEV1 is significant, it is not believed to be sufficient to address unmet medical needs in COPD. To allow for evaluation of secondary endpoints in COPDCompEx, treatment will continue after primary endpoint data collection to collect additional events. A longer intervention period will also allow for exploratory evaluation of treatment effects on FEV1 beyond week 12.

[0121] The secondary endpoint is COPDCompEx at week 28. Change in pre-BD clinical FEV1 will also be assessed at week 28.

[0122] Blood samples are collected from subjects for assessment of biomarkers related to disease pathology and / or the mechanism of action of MEDI3506.

[0123] result The maximum dose of MEDI3506 administered to subjects in this Phase 2 clinical trial is 600 mg administered by SC injection Q4W. This dose is intended to maximize the steady-state concentration (C max,ss The 600 mg dose administered by SC injection Q4W is predicted to result in lower exposure than the highest dose administered in the Phase 1 clinical trial (Study D9180C00001) (i.e., a single dose of 300 mg IV MEDI3506) in terms of C (approximately 2.5-fold) and AUC (approximately 1.6-fold). The 600 mg dose administered by SC injection Q4W is predicted to result in higher C compared to the highest multiple dose administered in the same trial (i.e., 300 mg SC Q2W). max,ss , but are predicted to have the same AUC (Table 6).

[0124] The nature and severity of the disease in the study population is not expected to significantly affect overall exposure or clearance. Published PK data for monoclonal antibodies approved for use in AD indicate that disease status (i.e., healthy subjects vs. subjects with AD) did not significantly affect exposure or clearance (Kovalenko et al., 2016). Therefore, we expect MEDI3506 to exhibit a similar PK profile in both healthy subjects and subjects with COPD.

[0125] Example 3 - Dose Selection Criteria for MEDI3506 in the Treatment of COPD To select the target dose, a PK / PD model was generated using target engagement data from the Phase 1 study (NCT03096795). More specifically, the PK / PD model: Based on quantitative information on MEDI3506:IL33 and IL33:ST2 complexes in the systemic circulation from Phase 1. The concentrations of both complexes were measured using a proprietary IL-33 detection reagent that specifically binds reduced IL-33 (redIL-33). PK data for MEDI3506 from Phase 1 (linear PK, half-life (t 1 / 2 is the 17th) Additional preclinical information that informed dose selection included: ● redIL-33:ST2 signaling pathway • oxIL-33:RAGE:EGFR signaling pathway is involved.

[0126] redIL-33:ST2 signaling pathway A mouse model of Alternaria alternata (ALT)-induced airway inflammation has been previously described (Kouzaki et al., J. Immunol. 2011, 186:4375-4387; Bartemes et al., J. Immunol. 2012, 188:1503-1513). Endogenous IL-33 is rapidly released after ALT exposure and drives IL-33-dependent IL-5 production in the lungs. Male or female wild-type or humanized IL-33 mice (6–10 weeks old) were briefly anesthetized with isofluorane and administered either 25 μg of ALT extract (Greer, Lenoir, NC) or vehicle intranasally in a total volume of 50 μL. Mice were treated intraperitoneally with MEDI3506 (0.1, 1, 2, or 10 mg / kg), isotype control IgG (NIP228), or vehicle (PBS, 10 mL / kg) 24 hours before intranasal challenge with ALT. 24 hours after challenge, mice were terminally anesthetized with sodium pentobarbital before exsanguination and bronchoalveolar lavage fluid (BALF) collection. BALF was collected by lavage via a tracheal cannula. BALF was centrifuged, cells were counted (total cells by FACS (FacsCALIBER, BD)), and supernatants were analyzed for cytokines by ELISA (Meso Scale Discovery, Rockville, MD). Differential cell counts (200 cells / slide) were performed on cytospin preparations stained with Diff-Quik (Fisher Scientific, UK). All work was carried out under the authority of the appropriate project license and in accordance with UK Home Office ethical and animal husbandry standards. Dose-dependent inhibition of IL5 by MEDI3506 was observed in BALF, with significant suppression achieved at 0.1 mg / kg, the lowest dose tested in this study. At 3 mg / kg, 90% inhibition was achieved, corresponding to a mean serum systemic exposure of 20 μg / mL in mice. The results are shown in Figures 5 and 6.

[0127] The oxIL-33:RAGE:EGFR signaling pathway is involved. Oxidized IL-33 (oxIL-33, IL-33ox, or IL-33DSB) has recently been discovered to directly impair epithelial repair responses, reducing epithelial goblet cell differentiation and proliferation, and increasing mucus production and the production of mucin-related genes such as MUC5AC. oxIL-33 was found to mediate its pathological effects on epithelia by binding to and signaling through the RAGE-EGFR complex (as described in WO 2021 / 089563, incorporated herein by reference).

[0128] The following MEDI3506 concentrations on the oxIL-33 signaling pathway were used to inform dose selection: Threshold for restoring oxIL-33-mediated dysfunctional scratch wound closure

[0129] Scratch wound closure Previous experiments have shown that oxIL-33 impairs epithelial scratch wound closure in healthy human bronchial epithelial cells (Figures 7A and 7B). The impaired wound closure was not restored by anti-ST2 antibody treatment, indicating that the pathological effect is mediated through the oxIL-33-RAGE / EGFR signaling axis. Scratch wound impairment was also observed in bronchial epithelial cells obtained from COPD subjects (Figure 8).

[0130] The concentration of MEDI3506 required to reverse oxIL-33-mediated excision wound closure dysfunction was calculated in A549 cell cultures.

[0131] A549 cells were obtained from ATCC and cultured in RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin and 10% FBS. Cells were harvested with Accutase (PAA, #L1 1-007) and cultured at 5 × 10 5Cells were seeded into 96-well plates at 100 μL per well and incubated at 37°C and 5% CO2 for 6–8 hours. The wells were then washed twice with 100 μL of PBS, followed by the addition of 100 μL of starvation medium (RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin) and incubation at 37°C and 5% CO2 for 18–24 hours. Cells were scraped using a WoundMaker™ (Essen Bioscience). The wells were then washed twice with 200 μL of PBS and then added with RPMI GlutaMax medium supplemented with 0.1% FBS (v / v) and 1% (v / v) penicillin / streptomycin containing the indicated stimuli; medium alone (unstimulated control), different concentrations of MEDI3506, or anti-TSLP antibody. The plates were then returned to 37°C and 5% CO2 for wound healing imaging and analysis over a 72-hour period. Relative wound density was calculated by the wound healing algorithm within Incucyte Zoom software. Figure 9 shows MEDI3506 dose-dependent improvement in scratch wound closure in A549 cells. A MEDI3506 concentration of greater than 50.4 pM (or 7.26 ng / mL) was required to achieve a complete response. This is assumed to correspond to a blood concentration of 0.15 μg / mL (assuming 5% distribution to the airway epithelial lining fluid after subcutaneous administration). No effect was seen with anti-TSLP antibodies.

[0132] Integrated PK / PD model for target engagement An integrated popPK / PD model was established based on SAD / MAD / IV MEDI3506 systemic exposure and target engagement (TE) clinical data from the MEDI3506 Phase 1 clinical trial. TE information used was systemic IL33-MEDI3506 complex formation and reduction in IL33-ST2 levels from FTIM.

[0133] The populations and doses included in the model include: Healthy subjects with mild atopy after a single subcutaneous (SC) dose (1-300 mg SC) and 300 mg intravenous (IV) administration • Included were patients with mild COPD receiving multiple doses of 30 mg, 100 mg, and 300 mg SC.

[0134] The model structure has four defined compartments and is shown in FIG.

[0135] The PKPD model reliably describes the observed PK profile of MEDI3506 in blood, MEDI3506:IL33 complex formation, and IL33:ST2 dose-dependent inhibition (Figures 11, 12, and 13). Figures 18 and 19 show different presentations of Figures 11 and 13, respectively. The solid lines represent the median observed values. The shaded areas represent the 95% confidence intervals of the median values ​​predicted by the model. The dashed lines represent the LLOQ values ​​for tozolaximab (0.01 ng / mL) and IL-33:sST2 (0.5 μg / mL), respectively.

[0136] The dose response of ST2:IL33 complex inhibition to MEDI3506 in blood at trough for Q2W, Q4W, and Q6W dosing regimens is shown in FIG.

[0137] The PK / PD model for IL-33 / sST2 complex inhibition in blood was further translated to predict IL-33 inhibition in lung tissue (assuming a blood:tissue partition coefficient of 14% and IL-33 levels in lungs 2-fold higher than in blood).

[0138] The % inhibition of IL-33 in lung tissue at trough versus dosing frequency for Q4W and Q8W is shown in Figure 15.

[0139] Dose Selection: Nearly 95% target inhibition in lung tissue at trough is predicted for a dosing frequency of 300 mg Q4W. MEDI3506 300 mg Q8W is predicted to achieve >80% TE in the lung, implying that sustained inhibition of IL-33 in patient lungs may be achievable using longer, more patient-friendly dosing intervals (Figure 15).

[0140] Based on the pharmacokinetic data and other input parameters, serum concentrations of MEDI3506 were modeled for 300 mg Q4W and 300 mg Q8W. Both of these regimens are predicted to have trough concentrations higher than the amount predicted by the Alternaria humanized IL-33 mouse model required to achieve 60% inhibition (Figure 16). The Alternaria model is more representative of acute effects caused by exacerbations or viral infections. Therefore, dose prediction using this cutoff is likely sufficient to achieve an effective dose for human chronic IL-33-mediated diseases such as COPD. Furthermore, both regimens are predicted to have trough concentrations higher than the threshold amount identified by the scratch wound model for inhibiting pathological signaling via the oxIL-33:RAGE / EGFR signaling axis (Figure 17).

[0141] Example 4 - A Phase III Multicenter, Randomized, Double-Blind, Chronic Administration, Parallel-Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Two Dose Regimens of MEDI3506 in Participants With Symptomatic Chronic Obstructive Pulmonary Disease (COPD) and a History of COPD Exacerbations Overall design The objective of this Phase 3 study was to evaluate the efficacy and safety of MEDI3506 at dose regimens of 300 mg every 8 weeks (Q8W) and 300 mg every 4 weeks (Q4W) administered subcutaneously (SC) in adult participants with symptomatic COPD and a history of two or more moderate exacerbations or one or more severe COPD exacerbations in the past 12 months. Participants must have been receiving optimized maintenance inhaled therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or contraindicated) for at least three months prior to enrollment.

[0142] The trial will randomize approximately 1,272 participants stratified by study region, maintenance inhaled therapy (dual vs. triple therapy), and smoking status (current vs. former smokers). The trial will include former and current smokers. Participants will continue their same COPD maintenance therapy throughout the study.

[0143] The trial consists of a screening period of at least 2 weeks, a 52-week treatment period (with site visits and IP administration every 4 weeks), and an 8-week post-treatment follow-up period.

[0144] The key primary and secondary objectives and endpoints are listed in the table below.

[0145] [Table 2-1]

[0146] [Table 2-2] AE = adverse event; BD = bronchodilator; CAT = COPD Assessment Trial; CCU = critical care unit; COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram; ED = emergency department; ER = emergency room; E-RS:COPD = Respiratory Symptoms Assessment in COPD; FEV1 = forced expiratory volume in 1 second; HRU = healthcare resource utilization; ICU = intensive care unit; IP = investigational drug; MCID = minimal clinically important difference; SGRQ = St. George's Respiratory Questionnaire; SoC = standard of care.

[0147] Participant type and disease characteristics 1. Documented diagnosis of COPD for at least 1 year prior to enrollment. 2 Post-BD FEV1 / FVC<0.70 and post-BD FEV1>20% of predicted normal (as assessed by central spirometry at screening). 3. Documented history of ≥2 moderate or ≥1 severe COPD exacerbation within 12 months prior to enrollment: (a) An exacerbation is considered moderate if it requires treatment with systemic corticosteroids and / or antibiotics and severe if it requires hospitalization. Note: Hospitalization is defined as inpatient admission for 24 hours or more in a hospital, observation area, emergency department, or other equivalent health care facility depending on the country and health care system. (b) At least one qualifying exacerbation was treated with systemic corticosteroids. (c) Events treated with antibiotics alone were considered moderate exacerbations only if antibiotics were prescribed specifically for worsening COPD symptoms. (d) Confirm that the previous exacerbation occurred while the participant was receiving ongoing dual or triple (ICS / LABA / LAMA) maintenance inhaled therapy for COPD and was not the result of a gap or step-down in treatment. (e) At least one qualifying exacerbation occurred during the most recent continuous, uninterrupted treatment prior to enrollment. 4. Documented optimal therapy with COPD maintenance therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or contraindicated) and continuous use for at least 3 months prior to enrollment. 5. Smoking history of 10 or more pack-years: (a) Former smokers were defined as participants who were not currently smoking and had quit smoking for 6 months or more prior to screening with the intention to quit permanently. (b) Current smokers were defined as participants who currently smoked cigarettes (at least one cigarette per day on average over the past 7 days) and were not currently participating in a smoking cessation program. (c) E-cigarette use does not contribute to the pack-year count toward eligibility. 6 CAT total score ≥ 10, with sputum (sputum) and cough items each scoring ≥ 2 at both screening and randomization. 7 At least 70% daily PRO completion during the entire screening period, and at least 50% daily PRO completion during the 14 days prior to randomization. 8 At least 70% adherence to COPD maintenance inhaled therapy (defined as taking COPD maintenance inhaled medication as scheduled for that day) during the entire screening period. 9. Can read and use electronic devices.

[0148] research intervention

[0149] [Table 3]

[0150] Rescue medication Short-acting beta-2 agonists (SABAs, e.g., salbutamol, albuterol, terbutaline, levalbuterol), short-acting muscarinic antagonists (SAMAs), SABA / SAMA combinations or alternative rescue medications may be used during the trial in the event of worsening COPD symptoms, according to local standard of care.

[0151] Maintenance therapy Continued optimized maintenance inhaled therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or contraindicated). The dose and regimen of other COPD maintenance therapies (e.g., xanthines, antibiotics, PDE4 inhibitors, etc.) will be continued for the 3 months prior to the study and throughout the study period.

[0152] Efficacy evaluation Assessment of COPD exacerbations For purposes of the clinical trial protocol, a COPD exacerbation is defined as a worsening of a participant's usual COPD symptoms (e.g., respiratory distress, sputum production, purulent sputum production, cough, wheezing, and other COPD-related symptoms and / or findings) that exceeds normal day-to-day variation, is acute in onset, lasts for more than two days (or less than two days if the exacerbation is so rapid and severe that the treating physician determines that intensification of treatment cannot be delayed), and may justify a change in routine medication. Use of systemic corticosteroids for at least 3 days; a single depot injection (IM) dose of corticosteroids is considered equivalent to a 3-day course of systemic corticosteroids. Use of antibiotics. Hospitalization due to COPD (defined as admission to a hospital, observation area, emergency department, or other comparable health care facility depending on the country and health care system for 24 hours or more). leading to either death or

[0153] An exacerbation is considered moderate if it requires treatment with systemic corticosteroids and / or antibiotics and does not meet the serious event criteria. An exacerbation is considered severe if it results in COPD hospitalization or death.

[0154] The onset of an exacerbation was defined as the start date of systemic corticosteroid or antibiotic treatment or hospitalization, whichever occurred first, and the end date was defined as the last day of systemic corticosteroid or antibiotic treatment or discharge, whichever occurred last. A single depot injection dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. Therefore, the corresponding stop date of this treatment was determined as the date of administration plus 2 days.

[0155] Spirometry (evaluation before and after administration of bronchodilators) All spirometry measurements are performed prior to administration.

[0156] Pulmonary function (FEV1 and FVC) will be measured by spirometry using equipment provided by a central vendor. Spirometry will be performed by the investigator or an authorized representative in accordance with American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (Graham et al., 2019).

[0157] Spirometry criteria Determine predicted normal values ​​(PNV) using the World Lung Function Initiative equation and pre-program it into the spirometer (Quanjer et al., 2012).

[0158] Forced expiratory volume in 1 second, expressed as a percentage of PNV, is calculated as follows: FEV1% of PNV = (FEV1 actual value / FEV1PNV) × 100 FEF 25~75% is calculated using a method similar to that for FEV1.

[0159] Spirometry after BD The maximum BD endpoint will be induced using albuterol (90 μg metered dose) or salbutamol (100 μg metered dose) with or without a spacer device, up to four puffs, within 30 ± 15 minutes of the final pre-BD spirometry test. Post-BD spirometry will be performed 15–30 minutes later. If participants cannot tolerate four puffs of albuterol or salbutamol, a lower number of puffs may be considered at the investigator's clinical discretion.

[0160] Patient-reported outcomes (PROs) Participants will complete the following non-daily PROs in this order: SGRQ, CAT, 5-level EuroQol-5 Dimension (EQ-5D-5L), Work Productivity and Activity Impairment-General Health (WPAI-GH), PGIS, and Patient Global Status Change (PGIC). For frequency of assessments, see SoA (Section 1.3).

[0161] Exacerbations of Chronic Obstructive Pulmonary Disease Tool - Patient-Reported Outcomes (EXACT-PRO) The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity, and duration of COPD exacerbations (Jones et al. 2011, Leidy et al. 2011). The instrument was developed for daily home administration using a handheld electronic device. Respondents are instructed to complete the diary each night immediately before bedtime and to answer questions while considering their "today's" experiences. Daily EXACT-PRO total scores range from 0 to 100, with higher scores indicating greater severity. Total score changes are used to identify the onset and recovery of exacerbation events as defined by EXACT-PRO. In identifying event onset and recovery, EXACT-PRO can provide information on the frequency and duration of events as well as the severity of the events.

[0162] Assessment of respiratory symptoms in COPD (E-RS) The E-RS:COPD is an 11-item PRO developed to assess the severity of respiratory symptoms in COPD (Leidy et al. 2014a, Leidy et al. 2014b). The E-RS:COPD is a subset of items from the EXACT-PRO. The E-RS:COPD was designed to be taken as part of the daily EXACT-PRO assessment. The E-RS total:COPD item responses calculate a total score ranging from 0 to 40, with higher scores indicating greater severity. In addition to the total score, symptom domain scores can be calculated by summing the responses of items within each domain for shortness of breath (5 items; score range: 0–17), cough and sputum (3 items; score range: 0–11), and chest symptoms (3 items; score range: 0–12). As with the total score, higher domain scores indicate greater severity. An individual score reduction of at least 2 points on the E-RS:COPD total score is considered meaningful and is used as the definition of a responder (Leidy et al., 2014a).

[0163] Breathlessness, Cough and Sputum Scale (BCSS) The BCSS is a three-item PRO that assesses the severity of shortness of breath, cough, and sputum production on a scale of 0 to 4 (Leidy et al. 2003a, Leidy et al. 2003b). Item scores are summed to calculate a total score, with higher scores indicating more severe symptoms.

[0164] St. George's Respiratory Questionnaire (SGRQ) The SGRQ is a 50-item PRO instrument developed to measure the health status of participants with airway obstructive diseases (Jones et al. 1991; Jones and Forde 2009). The questionnaire is divided into two parts: Part 1 consists of eight items regarding the severity of respiratory symptoms over the past four weeks, and Part 2 consists of 42 items related to the daily activities and psychosocial impact of an individual's respiratory condition. The SGRQ calculates a total score and three component scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health state and 0 representing the best possible health state. Similarly, component scores range from 0 to 100, with higher scores indicating greater impairment. An individual score reduction of at least four points in the SGRQ total score is considered significant and is used to support the definition of a responder. Specific details of the scoring algorithm are provided by the developers in the user manual (Jones and Forde 2009).

[0165] COPD Assessment Test (CAT) The CAT is an eight-item PRO developed to measure the impact of COPD on health status (Jones et al. 2009, Kon et al. 2014). This instrument uses a semantic differential 6-point response scale defined by contrasting adjectives to capture the impact of COPD. Content includes items related to cough, phlegm, chest tightness, shortness of breath when climbing hills / stairs, home activity limitations, confidence to go out, sleep, and energy. Each item response ranges from 0 to 5, with 0 representing the least impact on health status and 5 representing the most impact on health status. The CAT total score is the sum of the item responses, with a score range of 0 to 40, and higher scores indicate a greater impact of COPD on health status. An individual score reduction of at least 2 points on the CAT total score is considered meaningful and is used to support the definition of a responder (Kon et al. 2014).

[0166] 5-level EuroQol-5 Dimension(EQ-5D-5L) The EQ-5D-5L is a 5-level standardized instrument for use as a measure of health outcomes. It is applicable to a wide range of health conditions and treatments and provides a simple descriptive profile and a single index value for health status. The EQ-5D-5L consists of two ratings, a descriptive system, and a visual analog scale (VAS). The descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five severity levels: no problem, slight problem, moderate problem, severe problem, and extreme problem. An EQ-5D-5L index score can be calculated using an appropriate value set based on participants' responses to the five dimensions, as further described in the statistical analysis plan (SAP).

[0167] The EQ-5D VAS records respondents' self-rated health on a 20-cm, 0-100 vertical scale, with endpoints labeled "best imaginable health" and "worst imaginable health," with higher scores corresponding to better health. This information is used as a quantitative measure of health as judged by the individual respondent.

[0168] Work Productivity and Activity Impairment Questionnaire (WPAI-GH) The WPAI-GH (Version 2.0) is a self-administered tool consisting of six questions addressing absenteeism, presenteeism (reduced effectiveness at work), overall work productivity loss (absenteeism + presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI-GH outcomes are scored as percentage impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al., 1993).

[0169] Patient Global Impression of Severity (PGIS) The PGIS is a single item designed to capture participants' perception of overall COPD symptom severity at the time of creation, using a 6-point scale (0 - no symptoms to 5 - very severe).

[0170] Changes in Patient Global Status (PGIC) The PGIC is a single item designed to capture participants' perception of the change in their overall COPD symptoms from the first dose of IP using a 7-point scale (1 - much better to 7 - much worse).

[0171] Composite endpoint for COPD exacerbations (COPDCompEx) The composite endpoint for COPD exacerbations (COPDCompEx) is an endpoint based on combining exacerbations with daily PRO-defined events and study withdrawals (Vogelmeier et al., 2020). The COPDCompEx components are defined as follows: Exacerbation: An episode leading to one or more of the following: hospitalization, emergency room visit, treatment with systemic corticosteroids, or treatment with antibiotics. Daily PRO events: defined by threshold and slope criteria using the following PRO variables: individual items of the BCSS and rescue medication use.

[0172] Statistical considerations Primary endpoint The primary endpoint is the annualized incidence of moderate to severe exacerbations, which will be assessed for each dose of MEDI3506 versus placebo, first in the primary population (ex-smokers) and then in the total population of current and ex-smokers.

[0173] The moderate-to-severe exacerbation rate in each MEDI3506 dose regimen group will be compared to the moderate-to-severe exacerbation rate in the placebo group using a negative binomial model. The response variable in the model is the number of COPD exacerbations experienced by participants over the full double-blind 52-week treatment period. The model includes the covariates of treatment group, study region, maintenance inhaled therapy (triple or dual), and number of exacerbations in the previous year (1 vs. ≥ 2) as categorical factors, and the post-BD FEV1% predicted at screening and log screening blood eosinophil count as continuous covariates. The logarithm of the participant's corresponding follow-up time will be used as an offset variable in the model. In the overall population analysis, smoking status will also be included as a covariate.

[0174] The estimated treatment effect (i.e., incidence rates for each dose of MEDI3506 relative to placebo), corresponding 95% confidence intervals (CIs), and two-sided p-values ​​for incidence rates are presented. Also shown are models adjusted for exacerbation rates in each treatment group.

[0175] A course of treatment with systemic corticosteroids or antibiotics initiated within 7 days of completing a previous course of treatment is considered treatment for the same single exacerbation.

[0176] Secondary endpoints Analyses for all secondary endpoints will be performed in the primary population (ex-smokers). Similar analyses will be performed in the total population (ex-smokers and current smokers).

[0177] Time to first moderate or severe COPD exacerbation Time to first moderate or severe COPD exacerbation will be analyzed as the key secondary efficacy variable, with the primary objective being to explore the extent to which treatment with each dose of MEDI3506 delays the time to first exacerbation compared with placebo. Cox proportional hazards models will be fitted with covariates of treatment group, study region, maintenance inhaled therapy, number of exacerbations in the previous year, post-BD FEV1% predicted at screening, and log screening blood eosinophil count. Hazard ratios, 95% CIs, and p-values, as well as the proportion of participants with an event, will be reported.

[0178] St. George's Respiratory Questionnaire Change from baseline in SGRQ total score over 52 weeks will be compared between MEDI3506 and placebo using a repeated measures linear model. The dependent variable is the change from baseline in SGRQ total score at protocol-specified visits after baseline through the 52-week visit. Treatment, visit, treatment-visit interaction, study region, maintenance inhaled therapy, and number of exacerbations in the previous year will be fitted as categorical covariates, with baseline SGRQ total score, post-BD FEV1% predicted, and log screening blood eosinophil count as continuous covariates. An unstructured variance-covariance matrix will be used to model within-participant correlations. Contrasts will be used to generate treatment effect estimates at each visit (including weeks 24 and 52) and over 52 weeks, which will be reported along with two-sided 95% CIs and p-values.

[0179] Responder analyses will be performed on the SGRQ total score at week 52. Responders are defined as participants with an improvement (decrease) of 4.0 or more points compared to baseline. Participants who discontinue the study for any reason or have missing data at week 52 will be classified as non-responders. Logistic regression will be used to compare treatment groups with treatment, study region, maintenance inhaler therapy, and number of exacerbations in the previous year as categorical covariates, and post-BD FEV1% predicted, log screening blood eosinophil count, and baseline SGRQ total score as continuous covariates. P values ​​and odds ratios with 95% CI will be generated for each treatment comparison.

[0180] Change from baseline in E-RS: COPD total score Change from baseline in E-RS: COPD total score over 52 weeks will be analyzed using a model similar to that for change from baseline in SGRQ total score. Responder analysis of E-RS: COPD total score at week 52 based on a ≥2 point improvement (reduction) from baseline will also be constructed similar to the SGRQ responder analysis.

[0181] Change from baseline in pre-dose FEV1 The change from baseline in pre-dose / pre-BD FEV1 will be analyzed using a repeated measures model similar to the change from baseline in SGRQ score, but with treatment, visit, treatment-visit interaction, study region, maintenance inhaled therapy, and number of exacerbations in the previous year fitted as categorical covariates, and baseline FEV1 and log screening blood eosinophil count as continuous covariates. Contrasts will be used to generate treatment effect estimates at each visit (including weeks 24 and 52) and over 52 weeks, which are reported along with two-sided 95% CIs and p-values.

[0182] Other secondary endpoints The time to first severe exacerbation and the annual incidence of severe exacerbations will be analyzed in the same manner as for moderate or severe exacerbations above.

[0183] Analyses of change from baseline in CAT total score and the proportion of participants who achieved a 2 or more point decrease (improvement) in the CAT total score will be performed using methods similar to those for the SGRQ total score.

[0184] Example 5 - Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of MEDI3506 in Participants With Uncontrolled Moderate-to-Severe Asthma This example describes a Phase II, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of MEDI3506 in adult participants with moderate-to-severe asthma uncontrolled on standard of care (SOC). Participants will be randomized in a 1:1:1 ratio to receive 600 mg of MEDI3506, 300 mg of MEDI3506, or placebo every four weeks (Q4W) via subcutaneous (SC) injection for a total of four doses. Participants will be enrolled in the study for up to 29 weeks. The trial will consist of three periods, including a screening period of up to 5 weeks, a 16-week intervention period, and an 8-week follow-up period.

[0185] MEDI3506 (also referred to herein as 33_640087_7B) is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds to full-length and mature human IL-33 with very high affinity and prevents IL-33 from binding to the soluble (sST2) and membrane-bound ST2 (also known as IL-1RL1) receptor.

[0186] Several clinical and non-clinical studies have pointed to the IL-33 / ST2 signaling axis as playing an important role in the pathogenesis of asthma, and therefore, blocking this signaling pathway may be therapeutically beneficial in asthma.

[0187] The preclinical profile of MEDI3506 suggests that MEDI3506 can reduce asthmatic airway inflammation, improve epithelial integrity, decrease mucus production, and improve mucociliary transport. Therefore, MEDI3506 is hypothesized to affect the asthma disease state by increasing FEV1 (and other physiological measures of lung function), decreasing the frequency and severity of asthma exacerbations, and thereby improving quality of life.

[0188] Screening Procedure Participants will be assessed for study eligibility at Study Visit 1 (between days -35 and -28 of Study Visit 1). Participants whose asthma is assessed as uncontrolled at Study Visit 1 will undergo a further baseline assessment at Study Visit 1. Participants will then record adherence to their SOC asthma controller and acute medications for a minimum of 14 days (between days -14 and -6) before returning for Study Visit 2. Participants whose asthma remains uncontrolled despite acceptable adherence to their asthma controller treatment at Study Visit 2 (≥70% adherence [days] to controllers and ACQ-6 ≥ 1.5 as documented in the eDiary) will undergo a further screening assessment. Participants who continue to meet all eligibility criteria will be asked to participate in Study Visit 4 (randomization) 6–14 days after Study Visit 2.

[0189] Baseline measurements of ACQ-6, SGRQ, FeNO, pre-BD and post-BD spirometry assessments will be collected throughout the screening period.

[0190] Endpoints and Evaluation The primary efficacy endpoint was the effect of treatment compared with placebo on clinically measured lung function as measured by the change from baseline to week 16 in pre-BD FEV1(L).

[0191] Secondary endpoints include evaluation of the effect of treatment compared to placebo on asthma controls, as measured by change in ACQ-6 score from baseline to week 16. This includes measuring the proportion of subjects with a reduction in ACQ-6 score of 0.5 or greater from baseline to week 16. This also includes measuring the proportion of subjects achieving ACQ-6 well-controlled status (defined as an ACQ-6 score of 0.75 or less at week 16).

[0192] Evaluations will also include monitoring the effect of treatment compared to placebo on clinically measured lung function by change in post-BD FEV1(L) from baseline to weeks 8 and 16.

[0193] Secondary endpoints include assessment of the effect of treatment compared with placebo on CompEx (CompEx annualized event rate) based on the period from baseline to week 16.

[0194] Secondary endpoints include evaluation of the effect of treatment compared with placebo on FeNO levels, as measured by the percent change from baseline to week 16 in exhaled FeNO levels.

[0195] Additional endpoints to assess the longitudinal effects of treatment compared to placebo on asthma control and health status include: ● Change in ACQ-6 score from baseline to weeks 1, 4, 8, 12 and 24. ● Change in SGRQ score from baseline to weeks 4, 12 and 24. • Change from baseline to week 24 in the mean number of daily rescue medications used (puffs / day) over a 2-week period. Changes from baseline to weeks 4, 8, 12, 16, 20 and 24 in the following: o Asthma symptom score. Average number of nighttime awakenings.

[0196] Further endpoints to assess the effect of treatment compared to placebo on asthma-related inflammatory airway biomarkers include percent change in FeNO levels from baseline to weeks 1, 4, 8, 12, 16, 20 and 24.

[0197] The key primary and secondary objectives and endpoints are summarized in the table below.

[0198] [Table 4]

[0199] research intervention

[0200] [Table 5]

[0201] Rescue medication In the event of an asthma exacerbation during the study, systemic corticosteroid therapy may be used. Rescue medication use is permitted at any time during the study, but rescue medication use should be delayed, if possible, by at least 2 hours after administration of the study intervention. The date and time of rescue medication administration, as well as the name and administration regimen of the rescue medication, must be recorded.

[0202] Efficacy evaluation Spirometry (before and after bronchodilation) The World Lung Function Initiative prediction formula is used to determine PNV and is pre-programmed into the spirometer. FEV1, expressed as a percentage of PNV, is calculated as follows: FEV1% of PNV = (measured FEV1 / FEV1 PNV) x 100

[0203] Bronchodilation can be induced using up to four inhalations of albuterol (90 μg fixed dose), salbutamol (100 μg fixed dose), or levalbuterol (45 μg fixed dose). The use of a spacer device is strongly recommended for this procedure.

[0204] After a gentle, complete exhalation, salbutamol (100 μg fixed dose) or albuterol (90 μg fixed dose) should be administered using a spacer device, up to four times. In the rare case of an adverse or allergic reaction to albuterol / salbutamol, levalbuterol (45 μg fixed dose, up to four inhalations) can be used (Sorkness et al. 2008). Nebulizers should not be used. If there is any concern about any impact on the participant's safety, a lower total dose (e.g., two inhalations instead of four, and up to four puffs if necessary) can be used. The reason for this should be documented in the participant's medical record.

[0205] The highest pre- and post-BD FEV1 that is technically acceptable is used to determine reversibility. Reversibility is calculated as follows: FEV1% reversibility = (FEV1 after BD - FEV1 before BD) / FEV1 before BD × 100

[0206] Exhaled nitric oxide concentration Airway inflammation will be assessed using a standardized single-breath FeNO test. The single-breath technique recommended by the manufacturer is followed (Allakhverdi et al. 2007; Alving et al. 2017). The FeNO test will be performed before AO and spirometry. Participants should comply with relevant medication and other restrictions (sections 6.5.3 and 5.3) in advance. If these restrictions are not met and the assessment cannot be delayed until the day of the assessment, the assessment should be rescheduled within the permitted visit window.

[0207] FeNO will be measured using the NIOX VERO® Airway Inflammation Monitor. Instructions for use of this monitor will be provided in a separate user manual. NIOX VERO® sensors will be replaced according to the manufacturer's recommendations. The vendor supplying the equipment is responsible for ensuring that the equipment and procedures for measuring FeNO are validated prior to the start of the trial.

[0208] If possible, all post-randomization FeNO assessments should be performed within ±1.5 hours of the time FeNO randomization was performed.

[0209] Assessment and documentation of asthma exacerbations During the trial, an asthma exacerbation is defined as a change in a participant's usual asthma symptoms that results in any of the following: a. A temporary bolus / burst of systemic corticosteroids (or a temporary increase in a continuous OCS background dose) for at least 3 consecutive days to treat symptoms of asthma exacerbation; a single depot injectable dose of corticosteroids is considered equivalent to a 3-day bolus / burst of systemic corticosteroids. b. Emergency room or urgent care visit for asthma that required systemic corticosteroids (as above) (defined as evaluation and treatment in an emergency department or urgent care center within 24 hours). c. Hospitalization (defined as admission to an inpatient facility and / or evaluation and treatment in a health care facility for 24 hours or more).

[0210] Asthma exacerbation during hospitalization Defined as an asthma exacerbation resulting in (c) above. Note: For each exacerbation, the criteria to be met to confirm exacerbation status are: It should be documented. The following list defines acceptable documentation of past exacerbations: • Discharge abstract from hospital, emergency room, or urgent care facility indicating participant was admitted / treated with systemic corticosteroids for asthma exacerbation. • A signed, dated note from the referring physician containing information regarding the diagnosis of the exacerbation and treatment with systemic corticosteroids. • Evidence for prescribing systemic corticosteroids used during exacerbations. • A documented conversation between the investigator (or representative) and participants already participating in the OCS action plan, including the information needed to assess the inclusion criteria 19 . ● A documented conversation between the treating / referring physician or nurse / practice nurse verifying that the participant was treated for an exacerbation with corticosteroids at their clinic or under their supervision. Verbal confirmation of the date (month / year) of the exacerbation and that an appropriate prescription was provided is required. This option should only be used if reasonable attempts to obtain participant records have failed.

[0211] The following guidance defines the assessment of an asthma exacerbation.

[0212] The onset of an exacerbation was defined as the earliest of the following: • The start date of any temporary increase in systemic corticosteroid or continuous OCS background dose. • Date of emergency room or urgent care visit requiring systemic corticosteroids. ● Date of hospitalization for asthma.

[0213] The end date of the exacerbation was defined as the latest of the following: • Last day of temporary increase in systemic corticosteroid or continuous OCS background dose. • Date of discharge from the emergency room or emergency department. ● Discharge date.

[0214] If less than 7 days elapse between the end date of an asthma exacerbation and the start date of a new asthma exacerbation, the second event will be considered a recurrence of the previous asthma exacerbation in statistical analysis.

[0215] All asthma exacerbations occurring during treatment and follow-up must be recorded on the Exacerbation eCRF.

[0216] A persistent increase in asthma symptoms reported via the eDiary (that does not meet the criteria for an asthma exacerbation) will be graded as an asthma exacerbation. Specifically, an increase in rescue medication use of 4 or more puffs on at least 2 consecutive days compared with average use during baseline or 12 puffs / day on any one day; and / or • additional nebulized beta-2 agonist use on at least two consecutive days compared with average use during baseline, and / or an increase of 2 or more nights with asthma-related awakenings requiring rescue medication over a 7-day period compared with the mean during baseline; and / or Waking up due to asthma requiring rescue medication on at least 6 of the past 7 nights

[0217] A site alert will be generated for participants who experience a 30% or greater decline in PEF on two consecutive days.

[0218] If an asthma exacerbation event is not associated with at least one of the eDiary data exacerbation criteria above, the investigator must justify the decision to define the event as an exacerbation and record it on the eCRF. Events not supported by any objective assessment are considered not to be exacerbations as defined by the protocol.

[0219] CompEx CompEx is a combination of asthma exacerbations and diary events (i.e., a combination of eDiary variables). CompEx is a composite surrogate endpoint for asthma exacerbations recently developed by AstraZeneca (it is not yet a clinical endpoint approved by regulatory authorities). Diary events are defined by threshold and slope criteria using the following morning / evening (AM / PM) diary variables: ● PEF ● Symptom score (0-3) Use of rescue medication

[0220] CompEx can predict the effectiveness of treatment for exacerbations early in their course, before conducting traditional long-term exacerbation studies. CompEx can be widely used in the evaluation of new therapeutic interventions for asthma (Fuhlbrigge et al. 2017; Note: While the referenced publication used the term "severe exacerbation," this protocol used the same definition used for "exacerbation." Therefore, the term "exacerbation" is used in this section for the sake of internal consistency of the protocol.)

[0221] Participant-reported outcome (PRO) questionnaire Participants will complete the PRO questionnaire on the electronic device provided at the site. PRO questionnaires to be completed at the site visit should be completed before treatment administration and ideally before any discussion of health status or other study procedures, such as collection of laboratory samples, to avoid biasing participant responses to questions. All PRO assessments during the morning and evening home assessment periods must be completed within this set time period programmed into the device, and participants will be notified when it is time to respond to the questions.

[0222] Daily electronic diary (eDiary) During the trial, participants will be required to take regular asthma long-term controller medication and complete an electronic diary twice daily.

[0223] In SV1, participants will receive a handheld electronic diary device to complete twice-daily, once-daily, and non-daily PRO assessments during the study. Participants will be provided with training on the use of the handheld device. Daily assessments will include nighttime and daytime asthma symptoms (morning and evening diaries, respectively), use of inhaled rescue medication in response to symptom exacerbations, nights awake for asthma symptoms (morning diary only), and background medication use. PEF data (obtained from a home peak flow meter) will be captured at the completion of morning and evening electronic diary entries.

[0224] Daytime was defined as the time between the morning lung function assessment (upon awakening in the morning) and the evening lung function assessment. Nighttime was defined as the period between the evening lung function assessment (at bedtime) and the morning lung function assessment.

[0225] The number of rescue medication doses (1 dose unit = 1 puff from the inhaler) will be recorded twice daily by participants in their eDiary. The number of inhalations taken for lung function assessments between the morning and evening will be recorded in the evening.

[0226] The number of inhalations taken between the evening and morning pulmonary function assessments is recorded in the morning.

[0227] Nocturnal awakenings due to asthma symptoms will be recorded each morning in the daily eDiary by participants answering the question of whether they had been awakened at night due to asthma symptoms with a "yes" or "no" response.

[0228] Background treatment (inhaled ICS / LABA) medication use will be recorded once daily in the daily eDiary as a "yes" or "no" response.

[0229] Asthma Control Questionnaire-6 The ACQ (Juniper et al., 1999) was developed to measure asthma control and has been fully validated for use in adults and children aged 6 to 17 years. International guidelines for the treatment of asthma identify that the primary clinical goal of asthma control is to optimize asthma control (minimizing symptoms, activity limitations, bronchoconstriction, and rescue BD use), thereby reducing the risk of life-threatening exacerbations and long-term morbidity. The ACQ was developed to meet these criteria by measuring both the adequacy of asthma control and changes in asthma control that occur spontaneously or as a result of treatment.

[0230] The ACQ-6 asks participants to recall how their asthma has been over the past week by answering one BD use question and five symptom questions. Questions are equally weighted and scored from 0 (completely controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is the average of the responses. A mean score of 0.75 or less indicates well-controlled asthma, a score of 0.75 to 1.5 or less indicates partially controlled asthma, and a score above 1.5 indicates poorly controlled asthma (Juniper et al., 2006). An individual change of at least 0.5 is considered clinically meaningful.

[0231] St. George's Respiratory Questionnaire The SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstructive diseases (Jones et al. 1991). The questionnaire is divided into two parts: Part 1 consists of eight items regarding the severity of respiratory symptoms over the past four weeks. Part 2 consists of 42 items regarding the daily activities and psychosocial impact of the individual's respiratory condition. The SGRQ calculates a total score and three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health state and 0 representing the best possible health state. Similarly, domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details of the scoring algorithm are provided by the developers in the user manual (Jones and Forde 2009).

[0232] Statistical considerations Primary endpoint The difference in mean change from baseline (MEDI3506-placebo) in FEV1 at week 16 will be estimated using a repeated measures mixed-effects analysis of covariance model for the ITT population. The model includes all available data from all visits up to and including week 16, regardless of whether participants discontinued the study intervention or received rescue treatment. Because a repeated measures model is applied, missing data are not imputed. The model includes fixed effects for baseline, visit, treatment, and baseline by visit, as well as treatment by visit interaction. The significance of the treatment effect will be tested at a one-sided significance level of 10%.

[0233] Secondary and exploratory endpoints Changes from baseline in ACQ-6 and SGRQ parameters will be analyzed using a repeated measures analysis of covariance model similar to that described for the primary efficacy analysis. PRO responder endpoints at week 16 will be analyzed using chi-square tests.

[0234] The time to first CompEx event and time to first asthma exacerbation were analyzed using a Cox proportional hazards model, fitting treatment as a covariate. Data were also displayed in Kaplan-Meier plots. CompEx event rates were analyzed using negative binomial regression, with log(follow-up time) included as an offset term. The dependent variable was the number of CompEx events through week 16, and the model included treatment group as a fixed effect. All available data through week 16 from participants were included, regardless of whether they discontinued the study intervention.

[0235] Changes in FeNO concentrations from baseline to week 16 will be analyzed using a repeated measures analysis of covariance model similar to that described for the primary efficacy analysis. Endpoints may be log-transformed prior to analysis, if necessary. Least-squares mean changes from baseline for each treatment and estimates of the differences between them will be obtained from the model for each visit, along with 80% confidence intervals and one-sided p-values.

[0236] A repeated measures mixed effects analysis of covariance model similar to that described for the primary efficacy analysis will be used to estimate the difference in mean change from baseline in FEV1 after BD, and change in FEV1% reversibility at weeks 8 and 16.

[0237] The composite statistical estimate of interest is the difference between MEDI3506 and placebo response rates at week 16 in the ITT population. Participants with missing data at week 16 are considered non-responders. Odds ratios and 80% and one-sided p-values ​​are reported for each MEDI3506 group compared with placebo.

[0238] References Several publications are cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. Full citations for these references are provided below. Each of these references is incorporated herein in its entirety. Adeloye D,Chua S,Lee C,Basquill C,Papana A,Theodoratou E et al.Global and regional estimates of COPD prevalence:Systematic review and meta-analysis.J Glob Health.2015;5(2):020415. Allakhverdi Z,Comeau MR,Jessup HK,Yoon BR,Brewer A,Chartier S et al.Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes,trauma, or inflammation and potently activates mast cells.J Exp Med.2007;204(2):253-8. Allinne J,Scott G,Lim WK,Birchard D,Erjefalt JS,Sanden C et al.IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation.J Allergy Clin Immunol.2019;144(6):1624-37.e10. Alving K AR,Crater G,LaForce C F,Rickard K.Validation of a new portable exhaled nitric oxide analyzer,NIOX VERO:randomized studies in asthma.Pulm Ther.2017;3(1):207-18. Bonnelykke,Klaus et al.「A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.」Nature genetics vol.46,1(2014):51-5. Byers DE,Alexander-Brett J,Patel AC,Agapov E,Dang-Vu G,Jin X et al.Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.J Clin Invest.2013;123:9)3967-82. Celli BR,MacNee W,Force AET.Standards for the diagnosis and treatment of patients with COPD:a summary of the ATS / ERS position paper.Eur Respir J.2004;23(6):932-46. Donaldson GC,Seemungal TA,Bhowmik A,Wedzicha JA.Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.Thorax.2002;57(10):847-52. EMA.Guideline on Clinical Investigation of Medicinal Products in the Treatment of Chronic Obstructive Pulmonary Disease 2012[16 July 2021].Available from:https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-clinical-investigation-medicinal-products-treatment-chronic-obstructive-pulmonary-disease_en.pdf Accessed on:16 July 2021. Fuhlbrigge AL, Bengtsson T, Peterson S, Jauhiainen A, Eriksson G, Da Silva CA et al. A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomized controlled trials. The Lancet Respiratory medicine.2017;5(7):577-90. GOLD. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2020 Report 2020 [04 August 2020]. Available at: https: / / goldcopd.org / wp-content / uploads / 2019 / 12 / GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf. Accessed: August 4, 2020. Graham BL,Steenbruggen I,Miller MR,Barjaktarevic IZ,Cooper BG,Hall GL et al.Standardization of Spirometry 2019 Update.An Official American Thoracic Society and European Respiratory Society Technical Statement.Am J Respir Crit Care Med.2019;200(8):e70-e88. Guarascio AJ,Ray SM,Finch CK,Self TH.The clinical and economic burden of chronic obstructive pulmonary disease in the USA.Clinicoecon Outcomes Res.2013;5235-45. Gudbjartsson,Daniel F et al.「Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.」Nature genetics vol.41,3(2009):342-7. Hirota,Tomomitsu et al.「Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population.」Nature genetics vol.43,9 893-6.31 Jul.2011. Hochberg Y.A sharper Bonferroni procedure for multiple tests of significance.Biometrika.1988;75(4):800-2. Hopkins C,Gillett S,Slack R,Lund VJ,Browne JP.Psychometric validity of the 22-item Sinonasal Outcome Test.Clin Otolaryngol.2009;34(5):447-54. Jones PW,Quirk FH,Baveystock CM.The St George’s Respiratory Questionnaire.Respir Med.1991;85 Suppl B25-31;discussion 3-7. Jones PW,Forde Y.St George’s Respiratory Questionnaire Manual.2009;Version 2.3. Jones PW,Harding G,Berry P,Wiklund I,Chen WH,Kline Leidy N.Development and first validation of the COPD Assessment Test.Eur Respir J.2009;34(3):648-54. Jones PW,Chen WH,Wilcox TK,Sethi S,Leidy NK,Group E-PS.Characterizing and quantifying the symptomatic features of COPD exacerbations.Chest.2011;139(6):1388-94. Juniper EF,O’Byrne PM,Guyatt GH,Ferrie PJ,King DR.Development and validation of a questionnaire to measure asthma control.Eur Respir J.1999;14(4):902-7. Juniper EF,Bousquet J,Abetz L,Bateman ED,Committee G.Identifying’well-controlled’and’not well-controlled’asthma using the Asthma Control Questionnaire.Respir Med.2006;100(4):616-21. Kearley J,Silver JS,Sanden C,Liu Z,Berlin AA,White N et al.Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.Immunity.2015;42(3):566-79. Kemp SF,Lockey RF,Simons FE.World Allergy Organization ad hoc Committee on Epinephrine in A.Epinephrine:the drug of choice for anaphylaxis.A statement of the World Allergy Organization.Allergy.2008;63(8):1061-70. Kim V,Crapo J,Zhao H,Jones PW,Silverman EK,Comellas A et al.Comparison between an alternative and the classic definition of chronic bronchitis in COPDGene.Ann Am Thorac Soc.2015;12(3):332-9. Kim V,Zhao H,Regan E,Han MK,Make BJ,Crapo JD et al.The St.George’s Respiratory Questionnaire Definition of Chronic Bronchitis May Be a Better Predictor of COPD Exacerbations Compared With the Classic Definition.Chest.2019;156(4):685-95. Kon SS,Canavan JL,Jones SE,Nolan CM,Clark AL,Dickson MJ et al.Minimum clinically important difference for the COPD Assessment Test:a prospective analysis.Lancet Respir Med.2014;2(3):195-203. Lahousse L,Seys LJM,Joos GF,Franco OH,Stricker BH,Brusselle GG.Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease.Eur Respir J.2017;50(2). Leidy NK,Rennard SI,Schmier J,Jones MK,Goldman M.The breathlessness,cough,and sputum scale:the development of empirically based guidelines for interpretation.Chest.2003a;124(6):2182-91. Leidy NK,Schmier JK,Jones MK,Lloyd J,Rocchiccioli K.Evaluating symptoms in chronic obstructive pulmonary disease:validation of the Breathlessness,Cough and Sputum Scale.Respir Med.2003b;97 Suppl AS59-70. Leidy NK,Wilcox TK,Jones PW,Roberts L,Powers JH,Sethi S et al.Standardizing measurement of chronic obstructive pulmonary disease exacerbations.Reliability and validity of a patient-reported diary.Am J Respir Crit Care Med.2011;183(3):323-9. Leidy NK,Murray LT,Monz BU,Nelsen L,Goldman M,Jones PW et al.Measuring respiratory symptoms of COPD:performance of the EXACT-Respiratory Symptoms Tool(E-RS)in three clinical trials.Respir Res.2014a;15124. Leidy NK,Sexton CC,Jones PW,Notte SM,Monz BU,Nelsen L et al.Measuring respiratory symptoms in clinical trials of COPD:reliability and validity of a daily diary.Thorax.2014b;69(5):443-9. Leuppi JD,Schuetz P,Bingisser R,Bodmer M,Briel M,Drescher T et al.Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease:the REDUCE randomized clinical trial.JAMA.2013;309(21):2223-31. Mannino DM,Braman S.The epidemiology and economics of chronic obstructive pulmonary disease.Proc Am Thorac Soc.2007;4(7):502-6. Miravitlles M,Ribera A.Understanding the impact of symptoms on the burden of COPD.Respir Res.2017;18(1):67. Moffatt,Miriam F et al.「A large-scale,consortium-based genomewide association study of asthma.」The New England journal of medicine vol.363,13(2010):1211-1221. MullerovaH,Maskell J,Meeraus WH,Galkin D,Albers FC,Gait C.Characterization of COPD Patients Treated with Inhaled Triple Therapy Containing Inhaled Corticosteroids[ICS],Long-Acting Beta2-Agonists[LABA],and Long-Acting Muscarinic Antagonists[LAMA]in the UK.Am J Respir Crit Care Med.2017;195:A4986. Mutze T,Glimm E,Schmidli H,Friede T.Group sequential designs with robust semiparametric recurrent event models.Stat Methods Med Res.2019;28(8):2385-403. Okajima Y,Come CE,Nardelli P,Sonavane SK,Yen A,Nath HP et al.Luminal Plugging on Chest CT Scan:Association With Lung Function,Quality of Life,and COPD Clinical Phenotypes.Chest.2020;158(1):121-30. Parikh RH,Seliger SL,Christenson R,Gottdiener JS,Psaty BM,deFilippi CR.Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly,Community-Dwelling Population.J Am Heart Assoc.2016;5(8). Piccirillo JF,Merritt MG,Jr.,Richards ML.Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test(SNOT-20).Otolaryngol Head Neck Surg.2002;126(1):41-7. Quanjer PH,Stanojevic S,Cole TJ,Baur X,Hall GL,Culver BH et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range:the global lung function 2012 equations.Eur Respir J.2012;40(6):1324-43. Rabe KF,Martinez FJ,Ferguson GT,Wang C,Singh D,Wedzicha JA et al.Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.N Engl J Med.2020;383(1):35-48. Rabe KF,Celli BR,Wechsler ME,Abdulai RM,Luo X,Boomsma MM et al.Safety and efficacy of itepekimab in patients with moderate-to-severe COPD:a genetic association study and randomised,double-blind,phase 2a trial.Lancet Respir Med.2021. Radicioni G,Ceppe A,Ford AA,Alexis NE,Barr RG,Bleecker ER et al.Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease:an analysis of the SPIROMICS cohort.Lancet Respir Med.2021. Reilly MC,Zbrozek AS,Dukes EM.The validity and reproducibility of a work productivity and activity impairment instrument.Pharmacoeconomics.1993;4(5):353-65. Ritchie AI,Wedzicha JA.Definition,Causes,Pathogenesis,and Consequences of Chronic Obstructive Pulmonary Disease Exacerbations.Clin Chest Med.2020;41(3):421-38. Sampson HA,Munoz-Furlong A,Campbell RL,Adkinson NF,Jr.,Bock SA,Branum A et al.Second symposium on the definition and management of anaphylaxis:summary report--Second National Institute of Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol.2006;117(2):391-7. Schmitz J,Owyang A,Oldham E,Song Y,Murphy E,McClanahan TK et al.IL-33,an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.Immunity.2005;23(5):479-90. Seemungal TA,Donaldson GC,Paul EA,Bestall JC,Jeffries DJ,Wedzicha JA.Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med.1998;157(5 Pt 1):1418-22. Shrine,Nick et al.「Moderate-to-severe asthma in individuals of European ancestry:a genome-wide association study.」The Lancet.Respiratory medicine vol.7,1(2019):20-34. Smith D,Helgason H,Sulem P,Bjornsdottir US,Lim AC,Sveinbjornsson G et al.A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.PLoS Genet.2017;13(3):e1006659. Smith J,Owen E,Jones A,Dodd M,Webb A,Woodcock A.Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis.Thorax.2006;61(5):425-9. Soler-Cataluna JJ,Martinez-Garcia MA,Roman Sanchez P,Salcedo E,Navarro M,Ochando R.Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.Thorax.2005;60(11):925-31. Sorkness RL,Bleecker ER,Busse WW,Calhoun WJ,Castro M,Chung KF et al.Lung function in adults with stable but severe asthma:air trapping and incomplete reversal of obstruction with bronchodilation.J Appl Physiol(1985).2008;104(2):394-403. Stanczak MA,Sanin DE,Apostolova P,Nerz G,Lampaki D,Hofmann M et al.IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals.Nat Commun.2021;12(1):2133. Stone A.The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials.Pharm Stat.2010;9(2):151-61. Stott-Miller M,Mullerova H,Miller B,Tabberer M,El Baou C,Keeley T et al.Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort.Int J Chron Obstruct Pulmon Dis.2020;152467-76. Torgerson,Dara G et al.「Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.」Nature genetics vol.43,9 887-92.31 Jul.2011. Toy EL,Gallagher KF,Stanley EL,Swensen AR,Duh MS.The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition:a review.COPD.2010;7(3):214-28. van Manen JG,Bindels PJ,Dekker FW,Bottema BJ,van der Zee JS,Ijzermans CJ et al.The influence of COPD on health-related quality of life independent of the influence of comorbidity.J clin.epidemiol.2003;56(12):1177-84. Vestbo J,Papi A,Corradi M,Blazhko V,Montagna I,Francisco C et al.Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease(TRINITY):a double-blind,parallel group,randomised controlled trial.Lancet.2017;389(10082):1919-29. Vogelmeier CF,Fuhlbrigge A,Jauhiainen A,Scheepers L,Bengtsson T,Peterson S et al.COPDCompEx:A novel composite endpoint for COPD exacerbations to enable faster clinical development.Respir Med.2020;173106175. Wan,Y I et al.「Genome-wide association study to identify genetic determinants of severe asthma.」Thorax vol.67,9(2012):762-8.doi:10.1136 / thoraxjnl-2011-201262 Wedzicha JA,Seemungal TA.COPD exacerbations:defining their cause and prevention.Lancet.2007;370(9589):786-96. Corhay JL,Vincken W,Schlesser M,Bossuyt P and Imschoot J.Chronic bronchitis in COPD patients is associated with increased risk of exacerbations:a cross-sectional multicentre study.Int J Clin Pract 2013;67(12):1294-301. Crawford B,Monz B,Hohlfeld J,Roche N,Rubin B,Magnussen H,et al.Development and validation of a cough and sputum assessment questionnaire.Respir Med2008;102(11):1545-55. de Oca MM,Halbert RJ,Lopez MV,Perez-Padilla R,Talamo C,Moreno D,et al.The chronic bronchitis phenotype in subjects with and without COPD:the PLATINO study.Eur Respir J 2012;40(1):28-36. Jones PW and Forde Y.St George’s respiratory questionnaire manual.2009.Version 2.3. Kim V,Han MK,Vance GB,Make BJ,Newell JD,Hokanson JE,et al.The chronic bronchitic phenotype of COPD:an analysis of the COPDGene Study.Chest 2011;140(3):626-33. Kim V and Criner GJ.Chronic bronchitis and chronic obstructive pulmonary disease.Am J Respir Crit Care Med 2013;187(3):228-37. Martinez FJ,Calverley PM,Goehring U-M,Brose M,Fabbri LM,Rabe KF.Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy(REACT):a multicentre randomised controlled trial.Lancet 2015;358(9971):857-66. Monz BU,Sachs P,McDonald J,Crawford B,Nivens MC and Tetzlaff K.Responsiveness of the cough and sputum assessment questionnaire in exacerbations of COPD and chronic bronchitis.Respir Med 2010;104(4):534-41. NIH. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Source URL: https: / / aidsinfo.nih.gov / contentfiles / lvguidelines / adult_oi.pdf. Published in 2019. Access date: March 17, 2020. Smith J, Owen E, Earis J and Woodcock A. Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments. Chest 2006;130(2):379 - 85. Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med 2016;374(19):1811 - 21. For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press

[0239]

Table 6

Claims

1. 1. A method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose of about 300 to about 600 mg at intervals of every two weeks (Q2W), every four weeks (Q4W), or every eight weeks (Q8W), wherein the anti-IL-33 antibody is a. a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; b. a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:

7.

2. 1. A method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose effective to achieve at least 80% inhibition of IL-33 in the lung or airway epithelial lining fluid (ELF), wherein the anti-IL-33 antibody: a. a heavy chain variable region comprising a VHCDR1 having the sequence set forth in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; b. a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:

7.

3. 3. The method of claim 2, wherein said dose is effective to achieve at least about 90%, optionally at least 95%, inhibition of IL-33 in the lung.

4. 4. The method of claim 2 or 3, wherein the dose is about 300 to about 600 mg at intervals of every two weeks (Q2W), every four weeks (Q4W), or every eight weeks (Q8W).

5. 5. The method of any one of claims 1 to 4, wherein the dose is about 300 mg Q8W.

6. 5. The method of any one of claims 1 to 4, wherein the dose is about 300 mg Q4W.

7. 5. The method of any one of claims 1 to 4, wherein the dose is about 600 mg Q4W.

8. 5. The method of any one of claims 1 to 4, wherein the dose is about 300 mg Q2W.

9. The method of any one of claims 1 to 8, wherein the asthma is severe asthma.

10. The method according to any one of claims 1 to 8, wherein the asthma is moderate asthma.

11. The method of any one of claims 1 to 8, wherein the asthma is moderate to severe asthma.

12. 12. The method of claim 11, wherein the moderate to severe asthma is not controlled with standard therapy.

13. 13. The method of claim 12, wherein the standard of care is an asthma long-term controller medication treatment such as medium to high dose inhaled corticosteroids (ICS), defined as a total daily dose of more than 250 ug of fluticasone dry powder or equivalent, a long-acting muscarinic antagonist (LAMA), a leukotriene receptor antagonist (LTRA), theophylline, or an oral corticosteroid.

14. The method of any one of claims 1 to 13, wherein the subject is an adult.

15. The method of any one of claims 1 to 14, wherein the subject is a child or an adolescent.

16. The administration of １ The method of any one of claims 1 to 15, resulting in an increase in

17. 17. The method of any one of claims 1-16, wherein the administration results in a decrease in ACQ-6 score from baseline to week 16.

18. 18. The method of claim 17, wherein the reduction in ACQ-6 score from baseline to week 16 is 0.5 or greater.

19. 18. The method of claim 17, wherein the patient achieves ACQ-6 well-controlled status at 16 weeks.

20. 20. The method of any one of claims 1-19, wherein the administration results in a decrease in SGRQ score from baseline to week 16.

21. 21. The method of claim 20, wherein the decrease in SGRQ score from baseline to week 16 is 4 points or more.

22. 22. The method of any one of claims 1 to 21, wherein said administration results in a decrease in exhaled breath FENO concentration from baseline to 16 weeks.

23. The dose has a C of about 10 to 35 μg / mL during the administration period. ｍａｘ．ｓｓ 23. The method of any one of claims 1 to 22, which is effective to achieve

24. 24. The method of any one of claims 1 to 23, wherein the anti-IL-33 antibody or antibody variant thereof is selected from a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

25. The method of any one of claims 1 to 24, wherein the anti-IL-33 antibody or antibody variant thereof is IgG1.

26. The method of any one of claims 1 to 25, wherein the anti-IL-33 antibody or antibody variant thereof is a human antibody.

27. 27. The method of any one of claims 1 to 26, wherein the anti-IL-33 antibody or antibody variant thereof comprises a VH domain that is at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO:4 and a VL domain that is at least 95%, 90%, or 85% identical to the sequence set forth in SEQ ID NO:

8.

28. The method of any one of claims 1 to 27, wherein the anti-IL-33 antibody comprises a VH domain sequence set forth in SEQ ID NO:4 and a VL domain sequence set forth in SEQ ID NO:

8.

29. The method of any one of claims 1 to 28, wherein the anti-IL-33 antibody comprises a light chain sequence set forth in SEQ ID NO:9 and a heavy chain sequence set forth in SEQ ID NO:

10.

30. 30. The method of any one of claims 1 to 29, wherein the anti-IL-33 antibody variant has the same pharmacokinetic (pK) properties in humans as tozorakimab.

31. The method of any one of claims 1 to 30, wherein the anti-IL-33 antibody is tozolaximab.

32. The method of any one of claims 1 to 31, wherein the administration is subcutaneous.

33. The method of any one of claims 1 to 32, wherein the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 12 weeks.

34. The method of any one of claims 1 to 33, wherein the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 24 weeks.

35. The method of any one of claims 1 to 34, wherein the anti-IL-33 antibody or antibody variant thereof is administered for a period of at least 52 weeks.

36. 36. An anti-IL-33 antibody or antibody variant thereof characterized in any one of claims 1 to 35 for use in a method for treating asthma, wherein the method is a method characterized in any one of claims 1 to 35.

37. 37. Use of an anti-IL-33 antibody or antibody variant thereof as characterized in any one of claims 1 to 36 in the manufacture of a medicament for use in a method for treating asthma as characterized in any one of claims 1 to 36.

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