Asthma treatment methods

Abstract

The present disclosure relates to a method for treating a subject with moderate or severe asthma, a method for improving lung function in a subject with moderate or severe asthma, and a method for selecting a subject with moderate or severe asthma for treatment using the anti-IL-33 antibody tozorakimab.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 607,314 filed December 7, 2023. The entire contents of the aforementioned patent application are incorporated herein by reference.

[0003] Technology field

[0004] The present disclosure provides a method for treating moderate or severe asthma in a specific subgroup of patients. The method disclosed herein comprises the administration of an anti-IL-33 antibody or an antibody variant thereof, specifically tozorakimab. Background Technology

[0005] The following discussion is provided to assist the reader in understanding the present disclosure and does not constitute any acknowledgment of the content or relevance of the prior art.

[0006] Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and reversible airflow limitation. International treatment guidelines for asthma recommend ICS as a first-line treatment (GINA 2020). For patients who remain symptomatic despite intermediate-dose ICS monotherapy, step-escalation therapy with LABAs is the next recommended treatment option, followed by other controller therapies including leukotriene receptor antagonists, theophylline, and oral corticosteroids. 'Biological agents' that inhibit specific molecular targets, such as IgE or Th2 cytokines and their respective receptors (e.g., omalizumab and benralizumab), are used restrictively in patients with severely poorly controlled asthma. Furthermore, all currently approved asthma controller therapies have little to no effect on the natural course of the disease (i.e., most patients with moderate-to-severe asthma require lifelong treatment). There is a clear unmet need for asthma treatments that not only better control symptoms but also induce disease transformation.

[0007] Numerous studies have demonstrated the pivotal role of IL-33 in asthma. Genes encoding IL-33 and ST2 / IL1RL1 have been identified as major susceptibility loci for human asthma in several whole-genome 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]), and were among the few genes for which an association with asthma was reproducibly confirmed across various racial groups. Additionally, a rare IL-33 loss-of-function mutation that reduces blood eosinophil counts and protects against asthma has recently been reported ([Smith et al 2017]). The protective effect was maintained, albeit at a reduced level, even after adjusting for eosinophil counts, suggesting that IL-33 may influence asthma risk in part by regulating blood eosinophil counts and through additional biological pathways (Reference [Mousa et al 2017]). Two Phase II studies support the role of anti-IL-33 therapy in asthma treatment. In a proof-of-concept study in adult patients with moderate to severe asthma, REGN3500 (etokimab) monotherapy (ICS and LABA maintenance therapy were discontinued during the study period) met the primary endpoint of improved asthma control loss and also met the major secondary endpoint by significantly improving lung function compared to placebo (NCT03387852). In a separate Phase II clinical study, a single IV dose of etokimab was administered to patients with moderate to severe asthma whose condition was not controlled despite receiving high-dose combination ICS and LABA therapy. Asthma patients treated with etokimab showed significant improvement in lung function (FEV1) and a decrease in blood eosinophils compared to the placebo group (NCT03469934).

[0008] As with many other diseases, asthma patients exhibit significant variability in disease severity, onset, and rate of progression. Due to this extensive disease variability, different patient subgroups can receive the most appropriate benefits from distinct and more personalized treatments. Consequently, significant unmet medical needs remain.

[0009] The present disclosure aims to solve one or more problems in the aforementioned technical field. Accordingly, one or more aspects of the present disclosure and additional examples thereof are defined below.

[0010] Tozorakimab is a human IgG1 monoclonal antibody (mAb) that binds to human IL-33. Tozorakimab binds to the full-length and mature forms of human IL-33 with exceptionally high affinity and prevents IL-33 from binding to the soluble (sST2) and membrane-bound forms of the ST2 receptor (also known as IL-1RL1). Several clinical and nonclinical studies suggest that the IL-33 / ST2 signaling axis plays a key role in the pathogenesis of asthma. This disclosure describes the results of a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of tozorakimab in adult participants with moderate to severe asthma, where specific patient subgroups were identified.

[0011] In a first aspect, a method for treating a subject having moderate or severe asthma is provided, said method comprising the step of administering an effective amount of tozorakimab to said subject, said subject having experienced two or more asthma exacerbations during the 12 months prior to said administration.

[0012] In a second embodiment, a method for improving lung function of a subject having moderate or severe asthma is provided, said method comprising the step of administering an effective amount of tozorakimab to said subject, said subject having experienced two or more asthma exacerbations during the 12 months prior to said administration.

[0013] In a third embodiment, a method for increasing the BD-pre-FEV1 of a subject with moderate or severe asthma by at least 100 ml is provided, said method comprising the step of administering an effective amount of an IL-33 signaling axis antagonist to said subject, wherein said subject experienced two or more asthma exacerbations during the 12 months prior to said administration. Optionally, the method is a method for treating a subject with moderate or severe asthma by increasing the BD-pre-FEV1 of said subject by at least 100 ml.

[0014] In a fourth embodiment, a method for selecting a subject with moderate or severe asthma as a subject for treatment with an effective amount of tozorakimab is provided, the method comprising: determining the number of asthma exacerbations experienced by the subject during the past 12 months; and if the subject has experienced more than 2 asthma exacerbations during the past 12 months, selecting the subject as a subject for said treatment. Optionally, the method may further comprise the step of administering an effective amount of tozorakimab to the subject.

[0015] In the fifth aspect, tozorakimab is provided for use in the treatment of a subject with moderate or severe asthma, and the subject experienced two or more asthma exacerbations during the 12 months prior to the administration of tozorakimab.

[0016] In the 6th embodiment, tozorakimab is provided for use in improving lung function in a subject with moderate or severe asthma, and the subject experienced two or more asthma exacerbations during the 12 months prior to administration of tozorakimab.

[0017] In the seventh aspect, an IL-33 signaling axis antagonist is provided for use to increase the BD-pre-FEV1 of a subject with moderate or severe asthma by at least 100 ml, and the subject has experienced two or more asthma exacerbations during the 12 months prior to the administration of the IL-33 signaling axis antagonist. Alternatively, an IL-33 signaling axis antagonist is provided for use to treat the subject's moderate or severe asthma by increasing the BD-pre-FEV1 of a subject with moderate or severe asthma by at least 100 ml, and the subject has experienced two or more asthma exacerbations during the 12 months prior to the administration of the IL-33 signaling axis antagonist.

[0018] FRONTIER-3 (NCT04570657) is a Phase II, randomized, double-blind, placebo-controlled study to evaluate tozorakimab (MEDI3506) in asthma patients. This study demonstrates that while the primary endpoint was not met in the entire population, it was met in a specific patient subgroup. In particular, this study showed that participants who experienced at least two high exacerbations in the past year demonstrated an improved treatment response upon administration of tozorakimab. Surprisingly, this specific patient group showed improvement in lung function as measured by BD-pre-FEV1, with an increase in lung function of approximately 200 ml. This disclosure targets the treatment of the aforementioned patient subgroup who may benefit more from treatment with IL-33 signaling axis antagonists such as tozorakimab.

[0019] Additional features and examples of the modes defined above are described in the headings below. Each section may be combined in a combination compatible with any one of the modes mentioned above. Brief explanation of the drawing

[0238] Brief explanation of the drawing Specific details for implementing the invention

[0020] definition

[0021] The term “approximately” or “roughly” means an acceptable error for a specific value, as determined by a person skilled in the art, which depends in part on the method by which the value is measured or determined. In certain embodiments, the term “approximately” or “roughly” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “approximately” or “roughly” 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. Where the term “approximately” or “roughly” is placed before the first numerical value in a series of numerical values ​​consisting of two or more numerical values, the term “approximately” or “roughly” is understood to apply to each of the numerical values ​​in the series.

[0022] As used herein, "asthmatic exacerbation" or "asthmatic exacerbation" refers to a change in the subject's usual asthma symptoms, resulting in any of the following: (a) (i) a temporary bolus / burst administration of systemic corticosteroids for at least 3 consecutive days to treat the asthmatic exacerbation (or a temporary increase in the stable base dose of oral corticosteroids (OCS)); or (ii) a single storage injection of corticosteroids shall be considered equivalent to a 3-day bolus / burst administration of systemic corticosteroids; (b) an emergency room or urgent care visit due to asthma requiring such systemic corticosteroid administration (defined as receiving evaluation and treatment for less than 24 hours at an emergency room or urgent care center); or (c) hospital admission (defined as admission to an inpatient facility and / or receiving evaluation and treatment for 24 hours or more at a medical institution). "Asthma exacerbation accompanied by hospitalization" is defined as any asthma exacerbation leading to (c.) above.

[0023] It should be noted that the terms "a" or "an" refer to one or more of the corresponding entities; for example, "an anti-IL-33 antibody" is understood to refer to one or more anti-IL-33 antibodies. Accordingly, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably in this specification.

[0024] As used herein, the protein “IL-33” refers to interleukin 33, specifically mammalian interleukin 33 protein, and refers, for example, to the human protein registered as UniProt No. 095760. However, it is clear that this entity is not a single species but exists in reduced and oxidized forms. Given the rapid oxidation of the reduced form in vivo, for example, over a period of 5 to 40 minutes, and in vitro, references to IL-33 in the prior art may actually refer to the oxidized form. Additionally, commercial analytical methods may not effectively distinguish between the reduced and oxidized forms. The terms “IL-33” and “IL-33 polypeptide” are used interchangeably. In certain embodiments, IL-33 is the whole length. In other embodiments, IL-33 is the mature, cleaved IL-33 (amino acids 112-270). Recent studies suggest that full-length IL-33 is the active form (Cayrol and Girard, Proc Natl Acad Sci USA 106(22): 9021-6 (2009)]; Hayakawa et al., Biochem Biophys Res Commun. 387(1):218-22 (2009)]; Talabot-Ayer et al, J Biol Chem. 284(29): 19420-6 (2009)]). However, N-terminal treated or truncated IL-33s, including but not limited to aa 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, and 112-270, may have enhanced activity (Lefrancais 2012, 2014). In other embodiments, IL-33 may include full-length IL-33, a fragment thereof, or an IL-33 mutant or variant polypeptide, wherein the IL-33 fragment or IL-33 variant polypeptide retains some or all of the functional characteristics of the active IL-33.

[0025] As used herein, "reduced IL-33" or "redIL-33" refers to a form of IL-33 that binds to ST2 and triggers ST2-mediated signaling. In particular, the reduced forms of cysteine ​​208, 227, 232, and 259 are not disulfide-bonded.

[0026] It should be understood that references to "WT IL-33" or "IL-33" may mean either the reduced form or the oxidized form, or both, unless it is clear from the context in which they are used that a specific form is intended.

[0027] As used herein, the terms “treat” or “treatment” refer to both therapeutic interventions and prophylactic or preventive measures, the purpose of which is to prevent or delay (reduce) undesirable physiological changes or diseases. Beneficial or desirable clinical outcomes include, but are not limited to, relief of symptoms, reduction of disease range, stabilization of the disease state (i.e., non-deterioration), delay or slowing of disease progression, improvement or alleviation of the disease state, and partial or complete remission, regardless of detection. “Treatment” may also mean extending survival time compared to the survival time expected without treatment. Subjects requiring treatment include those who already have a disease or disability, as well as those prone to developing a disease or disability or those for whom the manifestation of a disease or disability must be prevented.

[0028] The terms “subject,” “individual,” “animal,” “patient,” or “mammal” mean any subject requiring diagnosis, prognosis, or treatment, in particular a mammalian subject, except where the subject is defined as a ‘healthy subject.’ Mammal subjects include humans, companion animals, and farm animals, e.g., dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, dairy cows, etc.

[0029] As used herein, "IL-33 signaling axis antagonist" means any agent that attenuates IL-33 activity. Suitablely, the IL-33 signaling axis antagonist may be selected from the group consisting of an antibody, its antigen-binding fragment, an aptamer, one or more heavy or light chain CDRs of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules. Suitablely, the IL-33 signaling axis antagonist is an antibody or its binding fragment. Suitablely, the IL-33 signaling axis antagonist is an anti-IL-33 antibody or its binding fragment. Suitablely, the anti-IL-33 antibody or its binding fragment specifically binds to IL-33.

[0030] The term "antibody" is used in its broadest sense and includes various immunoglobulin molecules and antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity. In particular, it includes full-length antibodies or molecules containing full-length antibodies, e.g., DVD-Ig molecules.

[0031] "Its binding fragment" is used interchangeably with "its antigen binding fragment" and refers to an epitope / antigen binding fragment of an antibody fragment, including, for example, a binding region, and in particular, including six CDRs, for example, three CDRs of a heavy chain variable region and three CDRs of a light chain variable region.

[0032] The terms "effective dose" or "therapeutically effective dose" of a formulation refer to, for example, tozorakimab, IL-33 signaling axis antagonists, or pharmaceutical formulations containing tozorakimab or IL-33 signaling axis antagonists, an amount sufficient to achieve a benefit or therapeutic effect, such as an amount to improve symptoms of a disease or condition, that is, an effective dose at the dosage and duration required to achieve a desired therapeutic or prophylactic outcome.

[0033] As used herein, the terms "complementary determining region" and "CDRs" refer to amino acid residues of the antibody or antigen-binding fragment responsible for antigen binding.

[0034] The term “immediately before administration” means up to 24 hours before administration, which includes, for example, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before administration.

[0035] The terms "FEV1 before BD," "FEV1 before BD," or "FEV1 before bronchodilator administration (BD)" refer to a forced expiratory volume of 1 before bronchodilator administration. This is the forced expiratory volume in 1 second of the subject measured before bronchodilator administration.

[0036] The term "BD-FEV1" or "Bronchodilator-Benefit (BD)-FEV1" means a forced expiratory volume of 1 after the administration of a bronchodilator. This is the forced expiratory volume in 1 second of the subject measured after the administration of a bronchodilator.

[0037] The term "pre-BD FVC" or "pre-BD forced vital capacity (FVC)" refers to the forced vital capacity prior to bronchodilator administration. This is the total volume of air exhaled by the subject during a forced expiratory volume test or FVC test prior to the administration of a bronchodilator.

[0038] The term "post-BD-FVC" or "post-BD-FVC" refers to forced vital capacity after the administration of a bronchodilator. This is the total volume of air exhaled by the subject during a forced expiratory volume test or FVC test after the administration of a bronchodilator.

[0039] The term "bronchodilator" refers to a substance that dilates the bronchi and bronchioles, thereby reducing resistance in the respiratory airways and increasing airflow to the lungs. Suitable bronchodilators include short-acting beta-agonists (SABAs) such as albuterol (90 1-1 g metered dose) or salbutamol (100 1-1 g metered dose) or equivalent substances (Sorkness et al, J Appl Physiol. 104(2):394-403, 2008).

[0040] The term "tidal volume" refers to the amount of air inhaled or exhaled during a subject's normal breathing.

[0041] The term "minute ventilation" refers to the total amount of air exhaled by a subject per minute.

[0042] The term "vital capacity" refers to the total amount of air a subject can exhale after inhaling as much as possible.

[0043] The term "functional residual volume" refers to the amount of air remaining in the lungs after a subject has exhaled normally.

[0044] The term "residual volume" refers to the amount of air remaining in the lungs after the subject has exhaled as much as possible.

[0045] The term "total lung capacity" refers to the total volume of the subject's lungs when filled with as much air as possible.

[0046] The term "forced expiratory flow rate" refers to the average velocity of the air flow rate exhaled by the subject during the middle half of the FVC test.

[0047] The term "Peak Expiratory Flow (PEF)" refers to the fastest rate at which a subject can force air out of their lungs during a forced expiratory volume (FEV) test or FVC test, and is typically measured in liters per minute (L / min).

[0048] The term "Forced Expiratory Volume (FEV)" refers to the amount of air exhaled by a subject during the first, second, and third seconds of an FVC test. As previously mentioned, the term FEV1 refers to the amount of air exhaled by a subject during the first second of an FVC test.

[0049] "Forced vital capacity (FVC)" or forced vital capacity testing measures the total volume of air exhaled forcefully and rapidly after a subject inhales as much as possible.

[0050] The term “placebo group” refers to a group of control subjects having the same characteristics as the subjects treated, which are subjects who have not received tozorakimab or an IL-33 signaling axis antagonist but have received a placebo. Appropriately, the placebo is a pharmacologically inactive preparation or composition. Appropriately, the placebo may contain the same components as the pharmaceutical composition containing tozorakimab or an IL-33 signaling axis antagonist, except that it does not contain an active tozorakimab or an IL-33 signaling axis antagonist.

[0051] object

[0052] Methods and medical uses are performed on a subject. Appropriately, the subject may be a human. Appropriately, the subject may be receiving medical treatment. Appropriately, the subject may be an individual requesting medical treatment. Appropriately, the subject is male or female. Appropriately, the subject is an adult or a child. Appropriately, the term "subject" is used interchangeably with the term "patient" herein.

[0053] Appropriately, the subject has asthma, is suspected of having asthma, or has symptoms consistent with asthma. Appropriately, a subject with asthma may mean a subject diagnosed with asthma. The subject may have a documented history of asthma, appropriately at least one year.

[0054] Appropriately, the subject has moderate or severe asthma, or moderate-to-severe asthma, or has symptoms consistent with moderate or severe asthma, or moderate-to-severe asthma. Appropriately, a subject having moderate or severe asthma, or moderate-to-severe asthma may mean a subject diagnosed with moderate or severe asthma, or moderate-to-severe asthma. The subject may have a documented history of moderate or severe asthma, or moderate-to-severe asthma, which, appropriately, may be at least one year. Appropriately, a reference in this institution that a subject has asthma may be interpreted as a reference that the subject has moderate or severe asthma.

[0055] Asthma is a chronic inflammatory disease of the airways affecting 1 to 18 percent of the population in various countries, characterized by bronchial hyperresponsiveness and reversible airflow limitation. Asthma is defined by a history of respiratory symptoms such as wheezing, dyspnea, chest tightness, and coughing. The etiology of asthma is considered multifactorial, and recognizable clusters of demographic, clinical, and / or pathophysiological phenotypes exist. Some phenotype-based therapies are available for patients with more severe phenotypes. However, a strong correlation between pathological symptoms, clinical features, and treatment response has not been established.

[0056] Different asthma subtypes have been identified, including allergic asthma, non-allergic asthma, late-onset asthma (generally having a non-allergic tendency), asthma with persistent airflow limitation (associated with airway wall remodeling and resulting in long-term, persistent, and irreversible airflow limitation), and asthma with obesity (generally associated with non- / hypoeosinophilic mechanisms of action). Appropriately, subjects treated by the present disclosure may have asthma of any type or origin.

[0057] In some embodiments, the subject may have early-onset asthma. "Early-onset" asthma as defined herein means a subject diagnosed with asthma before the age of 25, preferably before the age of 18. Diagnosis may be made by a clinician, for example, using any of the many well-known methods for diagnosing asthma. It should be understood that the methods for patients with early-onset asthma disclosed herein are not limited to subjects under the age of 25 (or even 18). For example, the treatment methods described herein may be used on adults (defined herein as persons over the age of 18), but the adult may have had asthma since before the age of 25.

[0058] There are different levels of asthma severity, which are retrospectively assessed based on the level of treatment required to control current symptoms and exacerbations. Severity indicators consist of three main groups: mild asthma, moderate asthma, and severe asthma. Asthma severity is defined on the GINA scale according to the level of treatment required to achieve adequate symptom control. The GINA scale is defined in the literature ["Pocket Guide for Asthma Management and Prevention," Global Initiative for Asthma; 2019]. Unless otherwise specified herein, references to "moderate asthma" or "severe asthma" follow the definitions of the GINA scale. For example, moderate asthma refers to asthma corresponding to GINA (Global Initiative for Asthma) scale 3 or lower, or appropriately GINA scale 2 or 3 (i.e., GINA stage 2 or stage 3), and severe asthma refers to asthma that requires high-intensity treatment (e.g., GINA stages 4 and 5) to maintain good control, or asthma in which good control is not achieved despite high-intensity treatment (Reference [GINA, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) December 2012]).

[0059] Appropriately, the subject treated by the present disclosure has moderate asthma, severe asthma, or moderate-to-severe asthma. In some embodiments, the subject has asthma that is not adequately controlled by standard treatment of a controller or symptom reliever as defined in steps 1 and 2 of the GINA scale. Accordingly, appropriately, the subject treated by the present disclosure may have uncontrolled asthma. Appropriately, the subject may have moderate asthma that is not controlled by standard treatment, severe asthma that is not controlled by standard treatment, or moderate-to-severe asthma that is not controlled by standard treatment. Standard treatment (SOC) regimens are as defined in the GINA scale.

[0060] Asthma can be diagnosed or evaluated by various measurement methods, including the following:

[0061] Airway inflammation evaluated using standardized single breath exhaled nitric oxide fraction (FeNO) (Reference [ATS, Am J Respir Crit Care Med. 171(8):912-30, 2005]). Although FeNO has not been established as a method to confirm the diagnosis of asthma, elevated FeNO is associated with asthma characterized by type 2 airway inflammation.

[0062] Determination of atopic status. This can be confirmed by skin prick tests using common environmental allergens or by measuring specific IgE levels in the serum. As with FeNO, allergy testing does not confirm or rule out a diagnosis of asthma, but the presence of atopy increases the likelihood that patients with respiratory symptoms have allergic asthma.

[0063] Bronchial provocation tests. These tests monitor variable airflow limitation to evaluate airway hyperresponsiveness (AHR). Subjects can be induced by chemical agents such as methacholine. These tests have moderate sensitivity for the diagnosis of asthma.

[0064] The Asthma Control Questionnaire (ACQ)-6 is a patient-reported questionnaire that assesses asthma symptoms (i.e., nocturnal awakening, symptoms upon waking, activity limitation, dyspnea, and wheezing), daily rescue bronchodilator use, and FEV1 (Reference [Juniper et al, Oct 1999]). The ACQ-6 is a shortened version of the original ACQ that excludes FEV1 measurements. Each item is assigned equal weight and scored from 0 (fully controlled) to 6 (severely poorly controlled). 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 greater than 1.5 indicates uncontrolled asthma (Reference [Juniper et al, Respir Med. 100(4):616-21, 2006]). An individual change of at least 0.5 is considered clinically significant (Reference [Juniper et al, Respir Med. 99(5):553-8, 2005]). Appropriately, subjects treated by the present disclosure may have an ACQ-6 score of 0.75 or higher, 0.80 or higher, 0.85 or higher, 0.90 or higher, 0.95 or higher, 1.0 or higher, 1.05 or higher, 1.10 or higher, 1.15 or higher, 1.20 or higher, 1.25 or higher, 1.30 or higher, 1.35 or higher, 1.40 or higher, 1.45 or higher, or 1.5 or higher prior to administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, subjects treated by the present disclosure may have an ACQ-6 score of 1.5 or higher prior to administration of tozorakimab or an IL-33 signaling axis antagonist.

[0065] Appropriately, lung function-related parameters described herein, such as FEV1 before BD, FEV1 after BD, FEV1, FVC before BD, FVC after BD, FVC, PEF, etc., are measured by spirometry. Appropriately, this may be home spirometry or clinic spirometry. Appropriately, unless otherwise specified, all spirometry is performed in a hospital.

[0066] Spirometry is performed in accordance with ATS / ERS (European Respiratory Society) guidelines (reference [Miller et al, Eur Respir J. 26(1):153-61, 2005]). For example, multiple forced expiratory trials (at least 3, but not exceeding 8) are performed in each spirometry session, and the two best trials that meet the ATS / ERS acceptance and reproducibility criteria are recorded. The best trials are determined based on the highest FEV1 value. The maximum forced expiratory volume (FEV1) from the two best trials is used for analysis. Both absolute measurements (for FEV1 and forced vital capacity (FVC)) and the percentage of predicted normal values ​​are recorded using appropriate reference values. The highest FVC value will be reported regardless of the trial in which it occurred (including even if the trial did not show the highest FEV1 value).

[0067] Post-BD spirometry is evaluated after the subject has performed pre-BD spirometry. Pre-BD FEV1 is measured using spirometry before administering an appropriate bronchodilator to the subject as defined above. To measure post-BD FEV1, maximal bronchodilation by a short-acting beta-agonist (SABA) is induced by using albuterol (90 1-1 g metered dose) or salbutamol (100 1-1 g metered dose) or an equivalent drug with a spacer device for a total of up to 8 inhalations (Sorkness et al, J Appl Physiol. 104(2):394-403, 2008). The highest pre-BD and post-BD FEV1 values ​​obtained after 4, 6, or 8 inhalations are used for the determination and analysis of reversibility. The reversibility algorithm is as follows: %Reversibility = (BD - Post-FEV1 - BD - Pre-FEV1) × 1 / BD - Pre-FEV1

[0068] Appropriately, the subject treated by the present disclosure may have a %reversibility of at least 12% and at least 200 ml (e.g., 15 to 60 minutes after four inhalations of albuterol / salbutamol).

[0069] Appropriately, during the 12 months prior to administration of tozorakimab or an IL-33 signaling axis antagonist, the subject experienced two or more asthma exacerbations. Appropriately, the subject to be treated by the present disclosure may have a specific blood eosinophil level of less than 300 cells / μl. In some embodiments, the specific blood eosinophil level is the blood eosinophil level determined prior to administration. This may also be referred to as the "baseline" of the blood eosinophil level. In some embodiments, the treatment method described herein may further include the step of selecting a subject having a specific blood eosinophil level. The subject may be selected from a group of subjects having a blood eosinophil level of less than 300 cells / μl. The results show that the patient's response to tozorakimab does not depend on the specific baseline blood eosinophil level (Figs. 5a and 5b). Nevertheless, a blood eosinophil level of less than 300 cells / μl is generally considered "low EOS." Subjects with low EOS asthma endotypes have particularly limited treatment options, even when considering currently approved biological agents.

[0070] In some embodiments, the blood eosinophil count is the blood eosinophil count measured immediately before administration of tozorakimab or the IL-33 signaling axis antagonist. The blood eosinophil count may be measured immediately before administration of tozorakimab or the IL-33 signaling axis antagonist. Appropriately, the blood eosinophil count is measured from a sample, appropriately a blood sample, collected from a subject or obtained within up to 24 hours prior to administration of tozorakimab or the IL-33 signaling axis antagonist.

[0071] Appropriately, the subject may be over 40 years of age. Appropriately, the subject may be under 75 years of age. Appropriately, the subject may be between 40 and 75 years of age. Appropriately, the subject may be between 40 and 45 years of age, 45 and 50 years of age, 50 and 55 years of age, 55 and 60 years of age, 60 and 65 years of age, 65 and 70 years of age, or between 70 and 75 years of age.

[0072] Appropriately, the subject can keep their vaccinations up to date, and appropriately, keep their vaccinations against respiratory diseases up to date. Appropriately, the subject has received pneumococcal and influenza vaccines.

[0073] Appropriately, the subject may have received treatment for asthma or may currently be receiving treatment for asthma. Appropriately, the subject may have or be receiving a documented, stable treatment regimen for asthma. Appropriately, said treatment may include one or more currently available asthma medications. Appropriately, the subject may have received or be currently receiving one or more of the following medications:

[0074] Inhaled corticosteroids such as fluticasone (Flovent HFA, Arnuity Ellipta, etc.), budesonide (Pulmicort Flexhaler), mometasone (Asmanex Twisthaler), beclomethasone (Qvar RediHaler), and ciclesonide (Alvesco)

[0075] Leukotriene modifiers such as montelukast (Singulair), zapyrlukast (Accolate), and xylutone (Zyflo)

[0076] ㆍ Sustained-release beta-agonists (LABAs) such as salmeterol (Serevent) and formoterol

[0077] ㆍ Long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat)

[0078] Combination therapies such as fluticasone and salmeterol (Advair Diskus, AirDuo Digihaler, etc.), budesonide and formoterol (Symbicort), mometasone and formoterol (Dulera), and fluticasone and vilanterol (Breo Ellipta)

[0079] Theophylline

[0080] Short-acting beta-agonists such as albuterol (ProAir HFA, Ventolin HFA, etc.) or levalbuterol (Xopenex HFA)

[0081] ㆍ Ipratropium (Atrovent HFA) or combination of ipratropium and albuterol (Combivent)

[0082] Oral corticosteroids such as prednisone or methylprednisolone

[0083] Appropriately, the subject may have received the above asthma treatment for more than 3 months.

[0084] Ideally, the subject may have a normal body mass index (BMI). Therefore, ideally, the subject has 19 kg / m² 2 Above and 35 kg / m² 2 The subject may have a BMI of 19 kg / m² or lower. Appropriately, the subject is 19 kg / m² 2 Above and 30 kg / m² 2 Below, 19 kg / m² 2 Above and 25 kg / m² 2 You may have a BMI below this level.

[0085] Treatment methods and lung function improvement methods

[0086] Appropriately, treatment of a subject with asthma as described herein results in an improvement in the subject's lung function. Therefore, appropriately, treatment of asthma in any of the treatment methods or medical uses described herein is achieved by improving the subject's lung function.

[0087] In some embodiments, the lung function of a subject may be compared to the lung function of a control subject. Appropriately, the control subject is an appropriately moderate or severe asthma subject who has not been treated with tozorakimab or an IL-33 signaling axis antagonist (this may be a subject from the placebo group).

[0088] Appropriately, improvement in lung function may be measured through pulmonary function tests such as spirometry and volumetric recording. Accordingly, appropriately, improvement in lung function may be any of the following: increased tidal volume, increased minute ventilation, increased vital capacity, increased functional residual capacity, increased residual capacity, increased total lung capacity, increased forced vital capacity (FVC), increased forced expiratory volume (FEV1) which may be increased FEV1 before BD or increased FEV1 after BD, increased forced expiratory flow rate, and increased peak expiratory flow rate (PEF); or alternatively, a reduction in the use of rescue medication or a reduction in the rate of exacerbations of the subject compared to an asthma subject who has not received tozorakimab or an IL-33 signaling axis antagonist, or appropriately, a subject with moderate or severe asthma (who may be a subject in the placebo group).

[0089] Alternatively, the subject's lung function may be compared to the same subject's baseline lung function, that is, lung function prior to administration of tozorakimab or the IL-33 signaling axis antagonist. Improvement in lung function may refer to an improvement in the subject's lung function following administration of tozorakimab or the IL-33 signaling axis antagonist, compared to baseline, i.e., prior to administration of tozorakimab or the IL-33 signaling axis antagonist. Therefore, appropriately, improvement in lung function may be any of the following: increased tidal volume, increased minute ventilation, increased vital capacity, increased functional residual capacity, increased residual capacity, increased total lung capacity, increased forced vital capacity (FVC), increased forced expiratory volume (FEV1) which may be increased FEV1 before BD or increased FEV1 after BD, increased forced expiratory flow rate, and increased peak expiratory flow rate (PEF), or alternatively, a reduction in the use of rescue medication or a reduction in the rate of deterioration of the subject compared to baseline measurements in the same subject, i.e., prior to administration of tozorakimab or an IL-33 signaling axis antagonist to the subject. Appropriately, this is performed immediately before administration of tozorakimab or an IL-33 signaling axis antagonist to the subject.

[0090] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma may result in an increase in the subject's pre-BD FEV1. The subject's pre-BD FEV1 may be compared to the pre-BD FEV1 of an asthma control subject (e.g., a subject in the placebo group) who has not received tozorakimab or an IL-33 signaling axis antagonist. Alternatively, the subject's pre-BD FEV1 may be compared to the baseline pre-BD FEV1 of the same subject, i.e., the pre-BD FEV1 prior to administration of tozorakimab or an IL-33 signaling axis antagonist to the subject.

[0091] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 100 ml in the subject's BD-pre-FEV1. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 100 ml in the subject's BD-pre-FEV1 compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 100 ml in the subject's BD-pre-FEV1 compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 100 ml in the subject's BD-pre-FEV1 compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0092] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's BD-pre-FEV1 by at least 105 ml, at least 110 ml, at least 115 ml, at least 120 ml, at least 125 ml, at least 130 ml, at least 135 ml, at least 140 ml, at least 145 ml, at least 150 ml, at least 155 ml, at least 160 ml, at least 165 ml, at least 170 ml, at least 175 ml, at least 180 ml, at least 185 ml, at least 190 ml, at least 195 ml, or at least 200 ml. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's BD-pre-FEV1 by at least 105 ml, at least 110 ml, at least 115 ml, at least 120 ml, at least 125 ml, at least 130 ml, at least 135 ml, at least 140 ml, at least 145 ml, at least 150 ml, at least 155 ml, at least 160 ml, at least 165 ml, at least 170 ml, at least 175 ml, at least 180 ml, at least 185 ml, at least 190 ml, at least 195 ml, or at least 200 ml compared to the control group or baseline.Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's BD-pre-FEV1 by at least 105 ml, at least 110 ml, at least 115 ml, at least 120 ml, at least 125 ml, at least 130 ml, at least 135 ml, at least 140 ml, at least 145 ml, at least 150 ml, at least 155 ml, at least 160 ml, at least 165 ml, at least 170 ml, at least 175 ml, at least 180 ml, at least 185 ml, at least 190 ml, at least 195 ml, or at least 200 ml at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist, compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's BD-pre-FEV1 by at least 105 ml, at least 110 ml, at least 115 ml, at least 120 ml, at least 125 ml, at least 130 ml, at least 135 ml, at least 140 ml, at least 145 ml, at least 150 ml, at least 155 ml, at least 160 ml, at least 165 ml, at least 170 ml, at least 175 ml, at least 180 ml, at least 185 ml, at least 190 ml, at least 195 ml, or at least 200 ml at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist, compared to the control group or baseline.

[0093] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of about 200 ml in the subject's BD-pre-FEV1. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of about 200 ml in the subject's BD-pre-FEV1 compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of about 200 ml in the subject's BD-pre-FEV1 compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of about 200 ml in the subject's BD-pre-FEV1 compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0094] In some embodiments, the increase in BD-pre-FEV1 of the subject is achieved by 16 weeks after administration of an effective amount of tozorakimab or an IL-33 signaling axis antagonist. In some embodiments, the increase in BD-pre-FEV1 of the subject is achieved by 24 weeks after administration of an effective amount of tozorakimab or an IL-33 signaling axis antagonist.

[0095] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma may result in an increase in the subject's hypothetical FEV1. Hypothetical FEV1 refers to the subject's FEV1 measured at home, and the subject's hypothetical FEV1 may be compared to the hypothetical FEV1 of an asthma control subject (e.g., a subject in the placebo group) who has not received tozorakimab or an IL-33 signaling axis antagonist. Alternatively, the subject's hypothetical FEV1 may be compared to the same subject's baseline hypothetical FEV1, i.e., the hypothetical FEV1 prior to administration of tozorakimab or an IL-33 signaling axis antagonist to the subject.

[0096] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 60 ml in the subject's hypothetical FEV1. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 60 ml in the subject's hypothetical FEV1 compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 60 ml in the subject's hypothetical FEV1 compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of at least 60 ml in the subject's hypothetical FEV1 compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0097] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's hypothetical FEV1 of at least 65 ml, at least 70 ml, at least 75 ml, at least 80 ml, at least 85 ml, at least 90 ml, or at least 95 ml. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's hypothetical FEV1 of at least 65 ml, at least 70 ml, at least 75 ml, at least 80 ml, at least 85 ml, at least 90 ml, or at least 95 ml compared to a control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's hypothetical FEV1 by at least 65 ml, at least 70 ml, at least 75 ml, at least 80 ml, at least 85 ml, at least 90 ml, or at least 95 ml compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's hypothetical FEV1 by at least 65 ml, at least 70 ml, at least 75 ml, at least 80 ml, at least 85 ml, at least 90 ml, or at least 95 ml compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0098] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of approximately 95 ml in the subject's hypothetical FEV1. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of approximately 95 ml in the subject's hypothetical FEV1 compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of approximately 95 ml in the subject's hypothetical FEV1 compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase of approximately 95 ml in the subject's hypothetical FEV1 compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0099] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma may result in an increase in the subject's PEF. The subject's PEF may be compared to the PEF of an asthma control subject (e.g., a subject in the placebo group) who has not received tozorakimab or an IL-33 signaling axis antagonist. Alternatively, the subject's PEF may be compared to the baseline PEF of the same subject, i.e., the PEF prior to administration of tozorakimab or an IL-33 signaling axis antagonist to the subject.

[0100] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of at least 5 L / min. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of at least 5 L / min compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of at least 5 L / min compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of at least 5 L / min compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of at least 5 L / min compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0101] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF by at least 5 L / min, at least 5.5 L / min, at least 6 L / min, at least 6.5 L / min, at least 7 L / min, at least 7.5 L / min, at least 8 L / min, at least 8.5 L / min, or at least 9 L / min. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF by at least 5 L / min, at least 5.5 L / min, at least 6 L / min, at least 6.5 L / min, at least 7 L / min, at least 7.5 L / min, at least 8 L / min, at least 8.5 L / min, or at least 9 L / min compared to a control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF by at least 5 L / min, at least 5.5 L / min, at least 6 L / min, at least 6.5 L / min, at least 7 L / min, at least 7.5 L / min, at least 8 L / min, at least 8.5 L / min, or at least 9 L / min at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist, compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF by at least 5 L / min, at least 5.5 L / min, at least 6 L / min, at least 6.5 L / min, at least 7 L / min, at least 7.5 L / min, at least 8 L / min, at least 8.5 L / min, or at least 9 L / min at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist, compared to the control group or baseline.

[0102] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of about 9 L / min. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of about 9 L / min compared to the control group or baseline. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of about 9 L / min compared to the control group or baseline at 16 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in an increase in the subject's PEF of about 9 L / min compared to the control group or baseline at 24 weeks after administration of tozorakimab or an IL-33 signaling axis antagonist.

[0103] In some embodiments, the increase in pre-BD-FEV1 or PEF of the subject is an increase relative to the baseline level. The baseline level may be the level in the asthmatic subject prior to administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. In some embodiments, the baseline level is the level in the same subject prior to administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist.

[0104] In some embodiments, treatment of a subject with asthma or improvement of lung function in a subject with asthma results in a reduction in the rate of exacerbation in the subject with asthma after administration of tozorakimab or an IL-33 signaling axis antagonist. In some embodiments, the rate of exacerbation is reduced by at least 10%, 15%, 20%, 25%, or at least 30%. Appropriately, the rate of exacerbation is reduced by at least 20%, at least 25%, or at least 30%. Appropriately, the rate of exacerbation is reduced by at least 10%, 15%, 20%, 25%, or at least 30% compared to the rate of exacerbation in an asthma control subject who has not received tozorakimab or an IL-33 signaling axis antagonist. Appropriately, the rate of exacerbation is reduced by at least 20%, at least 25%, or at least 30% compared to the rate of exacerbation in an asthma control subject who has not received tozorakimab or an IL-33 signaling axis antagonist. Appropriately, the aggravation rate is reduced by at least 10%, 15%, 20%, 25%, or at least 30% compared to subjects in the placebo group, or appropriately by at least 20%, at least 25%, or at least 30%. Alternatively, the aggravation rate is reduced by at least 10%, 15%, 20%, 25%, or at least 30% compared to the aggravation rate in the same subjects prior to administration of tozorakimab or an IL-33 signaling axis antagonist, or appropriately by at least 20%, at least 25%, or at least 30% compared to the aggravation rate during the 12 months prior to administration of tozorakimab or an IL-33 signaling axis antagonist.

[0105] In some embodiments, a reduction in the aggravation rate is achieved over a period of 16 weeks after administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. Optionally, a reduction in the aggravation rate is achieved up to 16 weeks after administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist.

[0106] Selection of objects

[0107] The present disclosure also relates to a method for selecting a subject with asthma as a treatment target. Optionally, other methods according to the present disclosure may further include the step of selecting a subject. Methods according to the present disclosure may simply include selecting a subgroup of subjects who can obtain greater benefit from the administration of tozorakimab or an IL-33 signaling axis antagonist compared to any subject.

[0108] Appropriately, the method for selecting a subject with asthma for treatment includes the step of determining the number of exacerbations the subject has experienced over the past 12 months. Appropriately, this can be determined through a patient survey or a review of medical records.

[0109] Appropriately, a method for selecting a subject with asthma for treatment includes a step of selecting the subject if the subject has experienced two or more exacerbations in the past 12 months.

[0110] Appropriately, a method for selecting a subject with asthma for treatment includes the step of selecting the subject if, during the 12 months prior to administration of tozorakimab or an IL-33 signaling axis antagonist, the subject has experienced 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more asthma exacerbations.

[0111] Appropriately, a history of past exacerbations, or appropriately a history of exacerbations during the 12 months prior to treatment, may be substantiated by any of the following: a discharge summary from a hospital, emergency room, or emergency care facility indicating that the subject was hospitalized or received systemic corticosteroid treatment due to an asthma exacerbation; a record signed and dated by the referring physician containing information regarding the diagnosis and treatment of the exacerbation with systemic corticosteroids; proof of the prescription of systemic corticosteroids used during the exacerbation; a documented conversation between the principal investigator or their delegate and the subject already included in the oral corticosteroid (OCS) implementation plan, containing information necessary to evaluate Inclusion Criterion 19; or a documented conversation with the treating physician / referring physician or nurse / specialist nurse confirming that the subject received treatment for the exacerbation using corticosteroids at the relevant clinic or under supervision. The date (month / year) of the exacerbation and verbal confirmation that an appropriate prescription was provided are required. This option should be used only when reasonable attempts to obtain the subject's records have been unsuccessful.

[0112] Appropriately, asthma exacerbations may be mild, moderate, or severe. Accordingly, appropriately, a method for selecting a subject with asthma for treatment includes the step of selecting the subject if the subject has experienced two or more mild, moderate, or severe asthma exacerbations during the 12 months prior to the administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, a method for selecting a subject with asthma for treatment includes the step of selecting the subject if the subject has experienced two or more moderate or severe asthma exacerbations during the 12 months prior to the administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, a method for selecting a subject with asthma for treatment includes the step of selecting the subject if the subject has experienced two or more severe asthma exacerbations during the 12 months prior to the administration of tozorakimab or an IL-33 signaling axis antagonist. An appropriate definition of "exacerbation" of asthma is as described above.

[0113] Appropriately, the method of selecting a treatment subject may further include the step of measuring the blood eosinophil levels of the subject, and appropriately, the blood eosinophil levels may be measured in a sample obtained from the subject. Appropriately, the sample is a blood sample. Appropriately, the method of selecting a subject with asthma as a treatment subject may further include an initial step of collecting or obtaining a sample from the subject. Appropriately, a blood sample may be collected or obtained from the subject. Appropriately, said sample is collected or obtained from the subject prior to the administration of tozorakimab or an IL-33 signaling axis antagonist, and appropriately, said sample is collected or obtained immediately before the administration of tozorakimab or an IL-33 signaling axis antagonist. Appropriately, said sample is collected or obtained from the subject within a maximum of 24 hours prior to said administration of tozorakimab or an IL-33 signaling axis antagonist.

[0114] Appropriately, a method for selecting a subject with asthma as a treatment target includes the step of selecting the subject when the subject's blood eosinophil count is less than 300 cells / μl.

[0115] Appropriately, a method for selecting a subject with asthma for treatment includes a step of selecting the subject when the subject is over 40 years of age. Appropriately, a method for selecting a subject with asthma for treatment includes a step of selecting the subject when the subject is under 75 years of age. Appropriately, a method for selecting a subject with asthma for treatment includes a step of selecting the subject when the subject is between 40 and 75 years of age. Appropriately, the subject may be between 40 and 45 years of age, 45 and 50 years of age, 50 and 55 years of age, 55 and 60 years of age, 60 and 65 years of age, 65 and 70 years of age, or between 70 and 75 years of age.

[0116] Appropriately, a method for selecting a subject with asthma as a treatment subject includes the step of selecting the subject when the subject keeps their vaccinations up to date, and appropriately includes the step of selecting the subject when the subject keeps their vaccinations against respiratory diseases up to date. Appropriately, a method for selecting a subject with asthma as a treatment subject includes the step of selecting the subject when the subject has received pneumococcal and influenza vaccines.

[0117] Appropriately, a method for selecting a subject with asthma as a treatment subject includes the step of selecting the subject if the subject has received or is currently receiving asthma treatment. Appropriately, a method for selecting a subject with asthma as a treatment subject includes the step of selecting the subject if the subject has received or is currently receiving a documented, stable treatment regimen for asthma. Appropriately, said treatment may include one or more currently available asthma treatments. Appropriately, the subject may have received or be currently receiving one or more of the following drugs:

[0118] Inhaled corticosteroids such as fluticasone (Flovent HFA, Arnuity Ellipta, etc.), budesonide (Pulmicort Flexhaler), mometasone (Asmanex Twisthaler), beclomethasone (Qvar RediHaler), and ciclesonide (Alvesco)

[0119] Leukotriene modifiers such as montelukast (Singulair), zapyrlukast (Accolate), and xylutone (Zyflo)

[0120] ㆍ Sustained-release beta-agonists (LABAs) such as salmeterol (Serevent) and formoterol

[0121] ㆍ Long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat)

[0122] Combination therapies such as fluticasone and salmeterol (Advair Diskus, AirDuo Digihaler, etc.), budesonide and formoterol (Symbicort), mometasone and formoterol (Dulera), and fluticasone and vilanterol (Breo Ellipta)

[0123] Theophylline

[0124] Short-acting beta-agonists such as albuterol (ProAir HFA, Ventolin HFA, etc.) or levalbuterol (Xopenex HFA)

[0125] ㆍ Ipratropium (Atrovent HFA) or combination of ipratropium and albuterol (Combivent)

[0126] Oral corticosteroids such as prednisone or methylprednisolone

[0127] Appropriately, a method for selecting a subject with asthma as a treatment subject includes the step of selecting the subject when the subject has received the asthma treatment for at least 3 months.

[0128] Appropriately, the method for selecting a subject with asthma for treatment includes the step of selecting the subject when the subject has a normal body mass index (BMI). Thus, appropriately, the subject has a BMI of 19 kg / m² 2 Above and 35 kg / m² 2 The subject may have a BMI of 19 kg / m² or lower. Appropriately, the subject is 19 kg / m² 2 Above and 30 kg / m² 2 Less than or equal to 19 kg / m³ 2 Above and 25 kg / m² 2 You may have a BMI below this level.

[0129] IL-33 signaling axis antagonist

[0130] Appropriately, tozorakimab or other IL-33 signaling axis antagonists described herein reduce, inhibit, or neutralize IL-33 activity. Interleukin-33 (IL-33), also known as IL-1F11, is a member of the interleukin-1 (IL-1) cytokine family encoded by the IL33 gene. IL-33 is a 270-amino acid protein composed of two domains: a homodomain and a cytokine (IL-1-like) domain. The homodomain contains a nuclear localization signal (NLS). IL-33 is known to exist in different forms; including a reduced form (redIL-33) and an oxidized form (oxIL-33). Previous studies have shown that the reduced form is rapidly oxidized under physiological conditions to form at least one disulfide bond with the oxidized form, and that these two forms may have different binding modes and effects.

[0131] IL-33 is constitutively expressed in various cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. Additionally, it has been reported that IL-33 expression can be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress and mechanical damage induced by environmental triggers such as allergens, toxins, and pathogens can induce the release of IL-33. Free IL-33 binds to a heterodimeric IL-33 receptor complex composed of tumor suppressor 2 (ST2) protein and interleukin-1 receptor helper protein (IL-1 RAcP), activating AP-1 and NF-κB pathways through the adapter protein Myeloid Differentiation Primary Response 88 (MyD88) and possibly MyD88-adapter-like (Mal) protein. IL-33 promotes immune responses by stimulating various cell types, including innate lymphocyte type II (ILC2) cells, mast cells, basophils, eosinophils, and dendritic cells. It was previously revealed that the reduced form of IL-33 binds to ST2 and is actually the only known ligand for the ST2 receptor expressed on Th2 cells and mast cells. Soluble ST2 (sST2) is thought to function as a decoy receptor that inhibits reduced IL-33 signaling.

[0132] The terms “Interleukin 1 Receptor-like 1 (IL1RL)” and “ST2,” used interchangeably herein, refer to natural ST2 derived from all vertebrates, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. ST2 is also referred to in the art as DER4, T1, and FIT-1. The term includes unprocessed ST2 of “full length” as well as all forms of ST2 generated by intracellular processing. At least four ST2 isoforms are known in the art, including soluble ST2 (sST2, also known as IL1RL1-a) and transmembrane ST2 (ST2L, also known as IL1RL1-b), generated by differential mRNA expression from a dual promoter system, and ST2V and ST2LV, generated by alternative splicing. The domain structure of ST2L consists of three extracellular immunoglobulin-like C2 It includes a domain, a transmembrane domain, and a cytoplasmic Toll / Interleukin-1 receptor (TIR) ​​domain. sST2 lacks the transmembrane and cytoplasmic domains present in ST2L and possesses a unique 9-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 for inhibiting soluble IL-33. The term also includes naturally occurring variants of ST2, such as splice variants (e.g., ST2V, which lacks a third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic variants. An exemplary amino acid sequence of human ST2 can be found, for example, under UniProtKB accession number 001638. ST2 is a co-receptor protein. IL-1 forms part of the IL-33 receptor along with RAcP.When IL-33 binds to ST2 and the co-receptor interleukin-1 receptor helper protein (IL-1 RAcP), a 1:1:1 trilateral signaling complex is formed to promote downstream signaling (Lingel et al. Structure 17(10):1398-1410, 2009; Liu et al. Proc. Nat. Acad. Sci. 110(37):14918-14924, 2013).

[0133] More recently, it has been revealed that the oxidized form of IL-33 also possesses physiological effects. It has been found that oxidized IL-33 does not bind to ST2 but instead binds to the receptor for advanced glycation end product (RAGE), transmitting signals through this alternative pathway. Surprisingly, it has been discovered that RAGE forms a complex with the epidermal growth factor receptor (EGFR) as part of the oxidized IL-33 pathway. Reduced IL-33 is rapidly converted to oxidized IL-33, which subsequently binds to RAGE and forms a complex with EGFR to stimulate EGFR activity. Antagonists capable of binding to either form of IL-33 are believed to effectively inhibit the signaling of oxidized IL-33. This can be achieved either by directly binding to oxidized IL-33 itself or indirectly by inhibiting the conversion of reduced IL-33 to oxidized IL-33; both methods consequently inhibit the stimulation of RAGE and EGFR.

[0134] Appropriately, "IL-33 signaling axis antagonist" means any molecule that inhibits or reduces the activity of any one of the components of a signaling pathway activated by IL-33, whether in its reduced or oxidized form. Appropriate signaling pathways activated by IL-33 may be the ST2 pathway or the RAGE pathway. Accordingly, appropriately, tozorakimab or other IL-33 signaling axis antagonists may inhibit or reduce the activity of any one of the components of the ST2 pathway and / or the RAGE pathway. Appropriately, in some embodiments, the IL-33 signaling axis antagonist may be an antibody, variant, or antigen-binding fragment thereof that inhibits or reduces the activity of one or more components of the ST2 pathway and / or the RAGE pathway.

[0135] As used herein, the "ST2 pathway" refers to the IL-33 / ST2 system in which reduced IL-33 is recognized by ST2, thereby promoting dimerization with IL-1RAcP at the cell surface, and recruiting receptor complex components MyD88, TRAF6, and IRAK1-4 to the intracellular TIR domain. Therefore, ST2-dependent signaling / effects can be interrupted or attenuated by interfering with the interaction between IL-33 and ST2, or alternatively by blocking the interaction with IL-1RAcP.

[0136] The "RAGE pathway" as used herein refers to the oxidized IL-33 / RAGE-EGFR system, which promotes the formation of a complex with EGFR within the cell membrane through the recognition of oxidized IL-33 by RAGE. Therefore, RAGE-EGFR-mediated signaling / effects can be interrupted and attenuated by interfering with the interaction between oxidized IL-33 and RAGE, or by blocking the conversion of reduced IL-33 to oxidized IL-33.

[0137] In this institution, antibodies, binding fragments, or antibody variants that specifically bind to and inhibit components of the IL-33 signaling axis are considered to be useful for the treatment of asthma. One example is the antibody tozorakimab. In another example, the antibody may be itepekimab. In yet another example, the antibody may be astegolimab.

[0138] Appropriately, tozorakimab or an IL-33 signaling axis antagonist is an antibody, variant, or antigen-binding fragment thereof that specifically binds to and inhibits one or more components of the IL-33 / ST2 signaling axis. Appropriately, tozorakimab or an IL-33 signaling axis antagonist is an antibody, variant, or antigen-binding fragment thereof that specifically binds to and inhibits the IL-33 receptor complex. Appropriately, tozorakimab or an IL-33 signaling axis antagonist is an antibody, variant, or antigen-binding fragment thereof that specifically binds to and inhibits ST2. Appropriately, tozorakimab or an IL-33 signaling axis antagonist is an antibody, variant, or antigen-binding fragment thereof that specifically binds to and inhibits IL-1 RAcP.

[0139] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist binds to IL-33 and inhibits it. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist is an antibody, variant, or antigen-binding fragment thereof that specifically binds to IL-33 and inhibits it.

[0140] Accordingly, appropriately, the tozorakimab or IL-33 signaling axis antagonist used herein is a binding molecule that can be selected from an antibody, its antigen-binding fragment, an aptamer, at least one heavy chain or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules.

[0141] Appropriately, tozorakimab or IL-33 signaling axis antagonists are any antibody or variant thereof that specifically binds to and inhibits IL-33, which is effective in treating asthma.

[0142] Appropriately, antibodies or their antigen-binding fragments include naturally occurring, polyclonal, monoclonal, recombinant, multispecific, mouse, human, humanized (e.g., complementarity determining region (CDR) grafted (CDR-grafted)), primateized, chimeric, and antibody variants, and may include single-stranded, monomeric antibodies and / or bispecific antibodies, as well as fragments or derivatives thereof.

[0143] Appropriately, the IL-33 signaling axis antagonist is an antibody or its antigen-binding fragment. Appropriately, the antigen-binding fragment may be an epitope-binding fragment, such as one containing Fab' and F(ab')2, Fd, Fv, single-stranded Fv (scFv), disulfide-bound Fv (sdFv), VL, or VH domains, or a fragment generated by a Fab expression library. Appropriately, Fab and F(ab') fragments may be generated by enzymatic cleavage of a full-length antibody. Other antigen-binding fragments include fragments generated by recombinant DNA technology, such as the expression of a recombinant plasmid containing a nucleic acid sequence encoding an antibody variable region. Appropriately, the antibody or its antigen-binding fragment may be a minibody, diabody, triabody, tetrabody, or single-stranded antibody. Appropriately, the antibody or its antigen-binding fragment is a monoclonal antibody. ScFv molecules are known in the art, for example, as described in U.S. Patent No. 5,892,019. In some cases, the anti-IL-33 antibody variant is selected from the group consisting of diabadies, triabadies, tetraabadies, Fab fragments, single-domain antibodies, and scFvs, wherein the dose is adjusted so that the binding site is equimolar to that administered by a divalent antibody.

[0144] Monoclonal antibodies may be modified for use as therapeutic agents or diagnostic agents. As used herein, "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides, including antibodies, bispecific antibodies, etc., having substantially the same amino acid sequence or derived from the same genetic origin. This term also includes antibody molecular preparations of a single molecular composition. Monoclonal antibody compositions exhibit single-binding specificity and affinity for specific epitopes.

[0145] One embodiment is a “chimeric” antibody, wherein a portion of the heavy chain (H) and / or light chain (L) is identical or homologous to a corresponding sequence of an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence of an antibody derived from a different species or belonging to a different antibody class or subclass. Additionally, fragments of such antibodies are also included insofar as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; reference [Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55].

[0146] In other cases, monoclonal antibodies are "humanized" antibodies. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patents No. 5,585,089 and No. 5,693,762. Generally, a humanized antibody is an antibody into which one or more amino acid residues of non-human origin have been introduced. Humanization can be performed, for example, by substituting at least a portion of a rodent complementarity determining region with a corresponding region of a human antibody, which can be performed using methods described in the art (References [Jones et al., 1986, Nature 321:522-25]; References [Riechmann et al., 1998, Nature 332:323-27]; References [Verhoeyen et al., 1988, Science 239:1534-36]).

[0147] The antibody molecules of the present disclosure may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, etc.), or subclass of immunoglobulin molecules. In one embodiment, tozorakimab or IL-33 signaling axis antagonist is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, tozorakimab or IL-33 signaling axis antagonist useful in the present method is a monoclonal IgG1 antibody.

[0148] In some embodiments, the IL-33 signaling axis antagonist is an anti-IL-33 antibody, an anti-ST2 antibody, an anti-IL1-RAcP antibody, a binding fragment, or a variant thereof. Appropriately, the anti-IL-33 antibody, variant, or binding fragment thereof specifically binds to IL-33, i.e., reduced or oxidized IL-33.

[0149] In some embodiments, the IL-33 signaling axis antagonist is an anti-IL-33 antibody, a binding fragment, or a variant thereof. Appropriately, any anti-IL-33 antibody, a binding fragment, or a variant thereof may be used in the method of the present disclosure.

[0150] Appropriately, the anti-IL-33 antibody, its binding fragment, or its antibody variant is 5 × 10 -2 M, 10 -2 M, 5 × 10 -3 M, 10 -3 M, 5 × 10 -4 M, 10 -4 M, 5 × 10 -5 M, 10 -5 M, 5 × 10 -6 M, 10 -6 M, 5 × 10 -7 M, 10 -7 M, 5 × 10 -8 M, 10 -8 M, 5 × 10 -9 M, 10 -9 M, 5 × 10-10 M, 10 -10 M, 5 × 10 -11 M, 10 -11 M, 5 × 10 -12 M, 10 -12 M, 5 × 10 -13 M, 10 -13 M, 5 × 10 -14 M, 10 -14 M, 5 × 10 -15 M or 10 -15 It specifically binds to redIL-33 with a binding affinity (Kd) of less than M. Suitablely, the binding affinity for redIL-33 is 5 × 10 -14 It is less than M (i.e., 0.05 pM). Suitablely, binding affinity is measured using a Kinetic Exclusion Assay (KinExA) or BIACORE™, and suitablely measured by KinExA using the protocol described in International Publication WO 2016 / 156440 (e.g., Example 11), the entire contents of which are incorporated herein by reference. With such binding affinity, anti-IL-33 antibodies, binding fragments, or antibody variants thereof that bind to redIL-33 appear to bind to redIL-33 strongly enough to prevent the dissociation of the binding molecule / redIL-33 complex within a biologically relevant time range. While we do not wish to be bound by theory, this binding strength is believed to prevent the release of the antigen before the antibody / antigen complex is degraded in vivo, resulting in redIL-33 not being released and unable to undergo the conversion from redIL-33 to oxIL-33. Therefore, when binding to redIL-33 with such binding affinity, anti-IL-33 antibodies, binding fragments, or antibody variants thereof can inhibit or weaken the activity of oxIL-33 by preventing the formation of oxIL-33.

[0151] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof is 10 3 M-1 candle -1 That is, 5 × 10 3 M -1 candle -1 That's all, 10 4 M -1 candle -1 10 or more or 5 × 10 4 M -1 candle -1 It can specifically bind to redIL-33 at a binding rate (k(on)) greater than or equal to 10. For example, the anti-IL-33 antibody of the present disclosure, the binding fragment, or the antibody variant thereof is 10 5 M -1 candle -1 That is, 5 × 10 5 M -1 candle -1 That's all, 10 6 M -1 candle -1 That is, 5 × 10 6 M -1 candle -1 10 or more 7 M -1 candle -1 It can bind to redIL-33 or its fragments or variants at a binding rate (k(on)) greater than or equal to 10. Suitablely, the k(on) rate is 10 7 M -1 candle -1 That is all.

[0152] Appropriately, the anti-IL-33 antibody, its binding fragment, or its antibody variant is 5 × 10 -1 candle -1 Below, 10 -1 candle -1 Below, 5 × 10 -2 candle -1 Below, 10 -2 candle -1 Below, 5 × 10 -3 candle -1 Less than or equal to 10 -3 candle -1 It can specifically bind to redIL-33 at a dissociation rate (k(off)) of less than or equal to 5 × 10-4 candle -1 Below, 10 -4 candle -1 Below, 5 × 10 -5 candle -1 Below, 10 -5 candle -1 Below, 5 × 10 -6 candle -1 Below, 10 -6 candle -1 Below, 5 × 10 -7 candle -1 Less than or equal to 10 -7 candle -1 It can be described as binding to redIL-33 or a fragment or variant thereof at a dissociation rate (k(off)) of less than or equal to 10. Suitablely, the k(off) rate is 10 -3 candle -1 The following describes IL-33. IL-33 is an alamin cytokine that is rapidly and in high concentrations released in response to inflammatory stimuli. RedIL-33 is converted to its oxidized form approximately 5 to 45 minutes after being released into the extracellular environment. Therefore, to prevent redIL-33 from being converted to oxIL-33, the anti-IL-33 antibodies, binding fragments, or antibody variants thereof described herein may bind to redIL-33 at these k(on) and / or k(off) rates. While not wishing to be bound by theory, these k(on) / k(off) rates are believed to allow the anti-IL-33 antibodies, binding fragments, or antibody variants thereof to rapidly bind to redIL-33 before it is converted to oxIL-33, thereby consequently reducing the formation of oxIL-33.

[0153] In various embodiments, the anti-IL-33 antibody, binding fragment, or antibody variant thereof may be an inhibitory antibody capable of inhibiting IL-33 or a fragment thereof as defined herein. In various embodiments, the inhibitory antibody may inhibit the binding of IL-33 or a fragment thereof to the IL-33 receptor complex, ST2, and / or IL-1 RAcP.

[0154] Anti-IL-33 antibodies suitable for use in the method of the present disclosure are known in the art and may include any one of the following anti-IL-33 antibodies: 33_640087-7B (described in International Publication WO 2016 / 156440), ANB020 known as etokimab (described in International Publication WO 2015 / 106080), 9675P (described in U.S. Patent Application Publication US 2014 / 0271658), A25-3H04 (described in U.S. Patent Application Publication US 2017 / 0283494), Ab43 (described in International Publication WO 2018 / 081075), IL33-158 (described in U.S. Patent Application Publication US 2018 / 0037644), 10C12.38.H6.87Y.581 IgG4 (described in International Publication WO 2016 / 077381) or a conjugated fragment thereof, each document incorporated herein by reference. All of these antibodies are listed in Table 1.

[0155] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a complementary determining region (CDR) of a variable heavy chain domain (VH) and a variable light chain domain (VL) pair selected from Table 1. Pair 1 corresponds to the VH and VL domain sequences of 33_640087-7B described in International Publication WO 2016 / 156440. 33_640087-7B is also known as tozorakimab. Pairs 2 through 7 correspond to the VH and VL domain sequences of antibodies described in U.S. Patent Application Publication US 2014 / 0271658. Pairs 8 through 12 correspond to the VH and VL domain sequences of antibodies described in U.S. Patent Application Publication US 2017 / 0283494. Pair 13 corresponds to the VH and VL domain sequences of ANB020 described in International Publication WO 2015 / 106080. Pairs 14 through 16 correspond to the VH and VL domain sequences of antibodies described in International Publication WO 2018 / 081075. Pair 17 corresponds to the VH and VL domain sequences of IL33-158 described in U.S. Patent Application Publication US 2018 / 0037644. Pair 18 corresponds to the VH and VL domain sequences of 10C12.38.H6.87Y.581 IgG4 described in International Publication WO 2016 / 077381.

[0156] [Table 1]

[0157]

[0158]

[0159]

[0160] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO. 1 and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO. 19. These CDRs correspond to CDRs derived from tozorakimab 33_640087-7B (described in International Publication WO 2016 / 156440), which binds to reduced IL-33 and inhibits its conversion to oxidized IL-33. Tozorakimab or 33_640087-7B is described in detail in International Publication WO 2016 / 156440, which is incorporated herein by reference.

[0161] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 7 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 25 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from antibody 9675P. 9675P is described in detail in U.S. Patent Application Publication US 2014 / 0271658, which is incorporated herein by reference.

[0162] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 11 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 29 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from antibody A25-3H04. A25-3H04 is described in detail in U.S. Patent Application Publication US 2017 / 0283494, which is incorporated herein by reference.

[0163] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 13 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 31 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from the antibody ANB020. ANB020 is described in detail in International Publication WO 2015 / 106080, which is incorporated herein by reference.

[0164] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 16 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 34 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from the antibody Ab43. Ab43 is described in detail in International Publication WO 2018 / 081075, which is incorporated herein by reference.

[0165] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 17 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 35 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from the antibody IL33-158. IL33-158 is described in detail in U.S. Patent Application Publication US 2018 / 0037644, which is incorporated herein by reference.

[0166] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof comprises a complementation determining region (CDR) of the heavy chain variable region (HCVR) comprising the sequence of SEQ ID NO: 18 (SEQ ID NO: 13) and a complementation determining region (CDR) of the light chain variable region (LCVR) comprising the sequence of SEQ ID NO: 36 (SEQ ID NO: 31). These CDRs correspond to CDRs derived from the antibody 10C12.38.H6.87Y.581 IgG4. 10C12.38.H6.87Y.581 IgG4 is described in detail in International Publication WO 2016 / 077381, which is incorporated herein by reference.

[0167] Appropriately, those skilled in the art are aware of available methods in the art for identifying CDRs within the heavy and light chain variable regions of antibodies or their antigen-binding fragments. Appropriately, those skilled in the art may perform, for example, sequence-based annotation. Since the regions between CDRs are generally highly conserved, logical rules can be used to determine the CDR locations. Those skilled in the art may use a series of sequence-based rules for conventional antibodies (Pantazes and Maranas, Protein Engineering, Design and Selection, 2010), and may alternatively or additionally correct these rules based on multiple sequence alignment. Alternatively, those skilled in the art may use the BLASTP command of BLAST+ to identify the most similar annotated sequence by comparing the antibody sequence with public databases operating based on Kabat, Chothia, or IMGT methods. Each of these methods devises a unique residue numbering scheme to assign numbers to the supervariable region residues and subsequently determine the start and end of each of the six CDRs according to specific key locations. For example, after aligning with the most similar annotated sequence, the CDR can be extrapolated from the annotated sequence to the unannotated sequence to verify the CDR. Examples of suitable tools / databases include the Kabat database, Kabatman, Scalinger, IMGT, and Abnum.

[0168] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) pair selected from Table 1.

[0169] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a VH domain having the sequence of SEQ ID NO. 1 and a VL domain having the sequence of SEQ ID NO. 19.

[0170] Appropriately, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises three CDRs within a heavy chain variable region according to SEQ ID NO. 1.

[0171] Appropriately, the anti-IL-33 antibody, binding fragment, or antibody variant thereof contains three CDRs within the light chain variable region according to SEQ ID NO. 19.

[0172] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises three CDRs in the heavy chain variable region according to SEQ ID NO. 1 and three CDRs in the light chain variable region according to SEQ ID NO. 19.

[0173] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a variable heavy chain domain (VH) and a variable light chain domain (VL) each comprising VH CDR 1 to 3 having the sequences of SEQ ID NO. 37, SEQ ID NO. 38, and SEQ ID NO. 39, wherein one or more VHCDRs have three or fewer single amino acid substitutions, insertions, and / or deletions.

[0174] Accordingly, suitably, the anti-IL-33 antibody, the binding fragment, or the antibody variant thereof comprises a VH domain comprising VHCDR 1 to 3 of SEQ ID NO. 37, SEQ ID NO. 38, and SEQ ID NO. 39, respectively.

[0175] Accordingly, suitably, the anti-IL-33 antibody, the binding fragment, or the antibody variant thereof comprises a VH domain comprising VHCDR 1 to 3, each consisting of SEQ ID NO. 37, SEQ ID NO. 38, and SEQ ID NO. 39.

[0176] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises a variable heavy chain domain (VH) and a variable light chain domain (VL), each comprising VL CDR 1 to 3 having the sequences of SEQ ID NO. 40, SEQ ID NO. 41, and SEQ ID NO. 42, wherein one or more VLCDRs have three or fewer single amino acid substitutions, insertions, and / or deletions.

[0177] Accordingly, suitably, the anti-IL-33 antibody, the binding fragment, or the antibody variant thereof comprises a VL domain comprising VLCDR 1 to 3 of SEQ ID NO. 40, SEQ ID NO. 41, and SEQ ID NO. 42, respectively.

[0178] Accordingly, suitably, the anti-IL-33 antibody, the binding fragment, or the antibody variant thereof comprises a VL domain comprising VLCDR 1 to 3, each consisting of SEQ ID NO. 40, SEQ ID NO. 41, and SEQ ID NO. 42.

[0179] Accordingly, suitablely, the anti-IL-33 antibody, the binding fragment, or the antibody variant thereof comprises VHCDR1 having the sequence of SEQ ID NO. 37, VHCDR2 having the sequence of SEQ ID NO. 38, VHCDR3 having the sequence of SEQ ID NO. 39, VLCDR1 having the sequence of SEQ ID NO. 40, VLCDR2 having the sequence of SEQ ID NO. 41, and VLCDR3 having the sequence of SEQ ID NO. 42.

[0180] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises VH and VL, wherein VH has an amino acid sequence that is at least 90%, e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to VH according to SEQ ID NO. 1.

[0181] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises VH and VL, wherein the disclosed VH has a sequence in which one, two, three, or four amino acids within the framework are deleted, inserted, and / or independently substituted with different amino acids.

[0182] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises VH and VL, wherein VL has an amino acid sequence that is at least 90%, e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to VL according to SEQ ID NO. 19.

[0183] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises VH and VL, wherein the disclosed VL has a sequence in which one, two, three, or four amino acids within the framework are independently deleted, inserted, and / or substituted with different amino acids.

[0184] S

[0185] Accordingly, an anti-IL-33 antibody, a binding fragment, or an antibody variant thereof comprises VH and VL, wherein VH has an amino acid sequence consisting of SEQ ID NO. 1 and VL has an amino acid sequence consisting of SEQ ID NO. 19.

[0186] In some embodiments, an anti-IL-33 antibody, binding fragment, or variant thereof useful for the present method comprises a heavy chain described in SEQ ID NO. 43 or a sequence 80%, 85%, 90%, or 95% identical thereto and / or a light chain described in SEQ ID NO. 44 or a sequence 80%, 85%, 90%, or 95% identical thereto. In some embodiments, the heavy chain has the sequence described in SEQ ID NO. 43, and the light chain has the sequence described in SEQ ID NO. 44. In some embodiments, an anti-IL-33 antibody, binding fragment, or variant thereof useful for the present method comprises a heavy chain consisting of the sequence described in SEQ ID NO. 43 and a light chain consisting of the sequence described in SEQ ID NO. 44.

[0187] In some embodiments, the IL-33 signaling axis antagonist is antibody 33_640087_7B disclosed in International Publication WO 2016 / 156440, which is incorporated herein by reference. 33_640087_7B is also referred to as MEDI3506 or tozorakimab in the art. Accordingly, in some embodiments of the present disclosure, the IL-33 signaling axis antagonist is tozorakimab.

[0188] Tozorakimab is a monoclonal antibody that binds to IL-33 and potently and specifically blocks all forms of IL-33, thereby preventing their signaling. Tozorakimab is an example of an IL-33 signaling axis antagonist. Tozorakimab also inhibits the conversion of redIL-33 to its oxidized form (oxIL-33), which has been shown to induce signaling via RAGE and epithelial cell proliferation. Appropriately, any of the characteristics defined above in relation to IL-33 signaling axis antagonists or anti-IL-33 antibodies also apply to tozorakimab.

[0189] Tozorakimab is an exemplary anti-IL-33 antibody comprising: (a) a heavy chain variable region comprising VHCDR1 having the sequence described in SEQ ID NO. 37, VHCDR2 having the sequence described in SEQ ID NO. 38, and VHCDR3 having the sequence described in SEQ ID NO. 39; and (b) a light chain variable region comprising VLCDR1 having the sequence described in SEQ ID NO. 40, VLCDR2 having the sequence described in SEQ ID NO. 41, and VLCDR3 having the sequence described in SEQ ID NO. 42.

[0190] Tozorakimab also includes a VH domain having the amino acid sequence described in SEQ ID NO. 1 and a VL domain having the amino acid sequence described in SEQ ID NO. 19.

[0191] Tozorakimab is an IgG1 antibody, and the sequences of the full-length heavy chain and light chain of tozorakimab containing the IgG1 chain are described in SEQ ID NOs 43 and 44, respectively.

[0192] Accordingly, in some embodiments, the antibody is tozorakimab or a binding fragment or variant thereof. Accordingly, in some embodiments, the IL-33 signaling axis antagonist is tozorakimab or a binding fragment or variant thereof. Accordingly, in some embodiments, the IL-33 signaling axis antagonist is tozorakimab.

[0193] In some embodiments, the IL-33 signaling axis antagonist is an anti-IL-33 antibody, binding fragment, or antibody variant thereof having pharmacokinetic (pK) properties similar or identical to tozorakimab in humans.

[0194] In particular, the anti-IL-33 antibody, conjugation fragment, or antibody variant thereof for use in the present method may have a half-life similar to or identical to tozorakimab in humans. An anti-IL-33 antibody, conjugation fragment, or antibody variant thereof having a half-life similar to or identical to tozorakimab 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, conjugation fragment, or antibody variant thereof having a half-life similar to or identical to tozorakimab 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. Anti-IL-33 antibodies, binding fragments, or antibody variants thereof having a half-life similar or identical to that of tozorakimab in humans 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.

[0195] In some embodiments, an IL-33 antibody, a binding fragment, or a variant thereof may competitively inhibit the binding of IL-33 to tozorakimab (described in International Publication WO 2016 / 156440). International Publication WO 2016 / 156440 discloses that tozorakimab binds to redIL-33 with particularly high affinity and attenuates both ST-2 and RAGE-dependent IL-33 signaling. An antibody, a binding fragment, or a variant thereof may be said to competitively inhibit the binding of a reference antibody to a corresponding epitope if it specifically binds to a specific epitope and blocks the binding of a reference antibody to said epitope to some extent. Competitive inhibition may be determined by any method known in the art, for example, competitive ELISA assays, DELFIA ®This can be determined by solid-phase assays such as the Dissociation-Enhanced Lanthanide Fluorescent Immunoassay (Perkin Elmer) and radioligand binding assays. For example, those skilled in the art may determine whether antibodies, binding fragments, or variants thereof compete for binding to IL-33 using in vitro competitive binding assays, such as the HTRF assay described in paragraphs 881 to 886 of International Publication WO 2016 / 156440, which are incorporated herein by reference. For example, those skilled in the art may label tozorakimab with a donor fluorophore and mix it at various concentrations with fixed-concentration samples of redIL-33 labeled with a recipient fluorophore. Subsequently, binding characteristics can be confirmed by measuring the fluorescence resonance energy transfer between the donor fluorophore and the recipient fluorophore within each sample. To identify competitive binding antibody molecules, those skilled in the art may first mix test binding molecules at various concentrations with fixed concentrations of the labeled tozorakimab antibody. Compared to a positive control containing only the labeled antibody, if the FRET signal decreases when the mixture is incubated with labeled IL-33, this indicates competitive binding to IL-33. It can be said that the antibody, binding fragment, or variant thereof competitively inhibits binding to a specific epitope of the reference antibody by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0196] Pharmaceutical composition

[0197] In some embodiments, an effective amount of tozorakimab or an IL-33 signaling axis antagonist is contained in a pharmaceutical composition comprising one or more excipients. Optionally, tozorakimab or an IL-33 signaling axis antagonist is administered to a subject in the form of a pharmaceutical composition.

[0198] Appropriately, the reference herein to 'tozorakimab or IL-33 signaling axis antagonist' may mean a pharmaceutical composition comprising tozorakimab or an IL-33 signaling axis antagonist. Appropriately, the pharmaceutical composition may comprise one or more IL-33 signaling axis antagonists.

[0199] Pharmaceutical compositions may be formulated with suitable carriers, excipients, and other formulation components that provide appropriate delivery, delivery efficiency, tolerability, etc. Many formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company (Eastern, Pennsylvania, USA), a prescription book known to all pharmaceutical chemists. Accordingly, in addition to the active ingredient (i.e., anti-IL-33 antibody), pharmaceutical compositions may include pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other substances well known to those skilled in the art. These substances must be non-toxic and must not interfere with the efficacy of the active ingredient. The specific properties of the carrier or other substances depend on the route of administration, which may be, for example, intravenous or subcutaneous injection.

[0200] In the case of subcutaneous injection, the pharmaceutical composition may be an aqueous solution having non-pyrogenic properties, appropriate pH, isotonicity, and stability.

[0201] The pharmaceutical composition may be in the form of a liquid formulation in the form of a container of a prescribed volume, including sealed and sterile plastic or glass vials, ampoules, and syringes, or in the form of a large-volume container such as a bottle. Appropriately, in the method described herein, the pharmaceutical composition is in the form of a liquid formulation.

[0202] Suitablely, the anti-IL-33 antibody may be present in the pharmaceutical composition at a concentration of 100 mg / ml to 200 mg / ml, and more suitablely at a concentration of 150 mg / ml. In particular, when a 300 mg antibody dose is used, the antibody (particularly tozorakimab) may be provided in the form of 2 ml of a 150 mg / ml liquid composition.

[0203] Suitablely, the anti-IL-33 antibody can be buffered to a pH of 5.2 to 5.7, most suitablely 5.5 (e.g., ±0.1). This choice of pH imparts significant stability to the pharmaceutical composition.

[0204] The reference to "pharmaceuticalally acceptable excipients" should be understood to include any excipients commonly used in pharmaceutical compositions. Such excipients may generally include one or more surfactants, inorganic or organic salts, stabilizers, diluents, solubilizers, reducing agents, antioxidants, chelating agents, preservatives, etc.

[0205] Appropriately, the surfactant is present in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w). Appropriately, the surfactant is polysorbate-80 (PS-80).

[0206] Anti-IL-33 antibodies (particularly tozorakimab) may be provided in the form of a pharmaceutical composition comprising L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride, and polysorbate 80. The composition may particularly comprise 20 mM ± 10% of L-histidine / L-histidine hydrochloride, e.g., 20 mM ± 2.5%, 5%, or 7.5% of L-histidine / L-histidine hydrochloride. That is, L-histidine / L-histidine hydrochloride may be present in the composition at a concentration of 18-22, 18.5-21.5, 19-21, or 19.5-20.5 mM, and suitably at a concentration of 20 mM.

[0207] The composition may particularly contain 220 mM ± 10% of L-arginine hydrochloride, for example, 220 mM ± 2.5%, 5%, or 7.5% of L-arginine hydrochloride. For example, L-arginine hydrochloride may be present in the composition at a concentration of 200-240, 205-235, 210-230, or 215-225 mM, and suitably at a concentration of 220 mM.

[0208] The composition may particularly include 0.03% w / v ± 10% of polysorbate 80, for example, 0.03% w / v ± 2.5%, 5%, or 7.5% of polysorbate 80. For example, polysorbate 80 may be present in the composition at a concentration of 0.027 to 0.033% w / v, 0.028 to 0.032% w / v, or 0.029 to 0.031% w / v, and suitably at a concentration of 0.03% w / v.

[0209] The composition may have a pH of 5.2 to 5.7, 5.3 to 5.6, or 5.4 to 5.5, and suitably may have a pH of 5.5.

[0210] In a specific embodiment, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, and 0.03% polysorbate 80, and has a pH of 5.5. Optionally, the pharmaceutical composition also comprises 150 mg / ml of tozorakimab. When the composition comprises 150 mg / ml of tozorakimab, a 300 mg dose of antibody may be administered with 2 ml of the composition.

[0211] Administration therapy

[0212] The present disclosure also relates to a regimen of administration of tozorakimab or IL-33 signaling axis antagonists that are particularly effective in the treatment of asthma.

[0213] The administration regimen consists of one or more controlled-size doses administered during the treatment period. If two or more doses are present, they are separated by administration intervals. Tozorakimab or IL-33 signaling axis antagonists are administered at therapeutically effective amounts. As defined above, the "effective amount" or "therapeutically effective amount" of a preparation, such as a pharmaceutical formulation containing an anti-IL-33 antibody, refers to an effective amount for the dose and duration required to achieve the desired therapeutic or prophylactic outcome.

[0214] Accordingly, in some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at a dose that achieves at least 80%, 85%, or 90% target binding in the lungs. In some embodiments, the dose achieves at least 90% target binding in the lungs. In some embodiments, the dose achieves at least 91%, 92%, 93%, or 94% target binding in the lungs. In some embodiments, the target binding rate % is achieved at the lowest concentration.

[0215] A method of administering tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof to a subject in need thereof is well known to those skilled in the art or can be easily determined by those skilled in the art and is described below.

[0216] The dose size of tozorakimab or IL-33 signaling axis antagonist may be expressed on a weight basis of tozorakimab or IL-33 signaling axis antagonist. In certain embodiments, tozorakimab or IL-33 signaling axis antagonist is administered at a dose of about 400 mg to about 800 mg, about 450 mg to about 750 mg, about 500 mg to about 700 mg, about 510 mg to about 690 mg, about 520 mg to about 680 mg, about 530 mg to about 670 mg, about 540 mg to about 660 mg, about 550 mg to about 650 mg, about 560 mg to about 640 mg, about 570 mg to about 630 mg, about 580 mg to about 620 mg, about 590 mg to about 630 mg, or about 600 mg. In some embodiments, the dose is 600 mg.

[0217] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist is formulated for subcutaneous injection at a concentration of 150 mg / mL, and a 600 mg dose is administered in a 4 mL therapeutic agent. A 600 mg dose of tozorakimab or an IL-33 signaling axis antagonist may be administered as two 300 mg doses administered simultaneously. As used herein, "simultaneous" doses mean doses administered simultaneously, or doses administered sequentially with no time interval between them or with only a minimum time interval (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 5 minutes).

[0218] In some embodiments, tozorakimab or IL-33 signaling axis antagonist is administered at a dose of about 200 mg to about 400 mg, about 250 mg to about 350 mg, about 260 mg to about 340 mg, about 270 mg to about 330 mg, about 280 mg to about 320 mg, about 290 mg to about 310 mg, about 295 mg to about 305 mg, or about 300 mg.

[0219] In some embodiments, the dose is 300 mg. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist is formulated for subcutaneous injection at a concentration of 150 mg / mL, so that a 300 mg dose is administered as a 2 mL therapeutic agent. In some embodiments, a 300 mg dose of tozorakimab or an IL-33 signaling axis antagonist may be administered as two 150 mg doses administered simultaneously. As used herein, "simultaneous" doses mean doses administered simultaneously, or doses administered sequentially with no time interval between them or with only a minimum time interval (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 5 minutes).

[0220] In some embodiments, the dose is 150 mg. In some embodiments, tozorakimab or IL-33 signaling axis antagonist is formulated for subcutaneous injection at a concentration of 150 mg / mL, so that a 150 mg dose is administered as a 1 mL therapeutic agent. The dose size of tozorakimab or IL-33 signaling axis antagonist may be expressed in terms of the plasma drug concentration provided by the dose, which may be expressed as the amount of active compound adjusted to provide a specific level of plasma drug concentration. Those skilled in the art may control plasma concentrations in the subject by varying the amount of antibody or variant administered, bioavailability, or the time / frequency of administration. Since plasma concentrations change over time due to the absorption and elimination of the drug, they may be expressed in various standardized ways, such as maximum values, minimum values ​​(lowest concentrations), or values ​​over the course of time.

[0221] In some embodiments, the dose is about 20 μg / mL to about 50 μg / mL, about 25 μg / mL to about 45 μg / mL, about 30 μg / mL to about 40 μg / mL, about 35 μg / mL to about 40 μg / mL, or about 37 μg / mL of C max,ssIt is selected to provide (maximum concentration observed under steady state). In some embodiments, C max,ss is a value observed during the administration period. In this context, "administration period" refers to the time between two consecutive administrations.

[0222] Serum tozorakimab concentrations can be measured using anti-drug antibody reagents to capture and detect tozorakimab from biological samples (e.g., blood) in appropriate assay formats (therefore C max,ss (It may be used for determination). In some embodiments, the analysis may use an anti-IgG1 capture monoclonal antibody (mAb) and a stabilized tozorakimab antigen labeled with a detectable label. The detectable label can be quantified, thereby allowing the concentration of tozorakimab to be determined. I

[0223] Administration of tozorakimab or an IL-33 signaling axis antagonist is performed in multiple doses separated by dosing intervals. In some embodiments, 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 embodiments, the dosing interval is approximately 4 weeks (i.e., 28 ± 4 days). In some embodiments, the dosing interval is approximately 2 weeks (i.e., 14 ± 4 days).

[0224] Accordingly, as used herein, a 600 mg dose with a 4-week dosing interval (Q4W) can be replaced with a 300 mg dose administered every 2 weeks (Q2W), both of which provide a dosing regimen equivalent to administering 600 mg every 4 weeks. Thus, in some embodiments, the dose is approximately 300 mg Q2W.

[0225] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject every 2 weeks (Q2W), every 4 weeks (Q4W), or every 8 weeks (Q8W).

[0226] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at about 300 mg Q2W. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at about 600 mg Q4W. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at about 300 mg Q4W.

[0227] In some embodiments, the effective amount of tozorakimab or IL-33 signaling axis antagonist is a dose in the range of 300 mg to 600 mg. The effective amount of tozorakimab or IL-33 signaling axis antagonist may be a tozorakimab dose of 300 mg to 600 mg.

[0228] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject at a dose of 600 mg every 4 weeks (Q4W). In some embodiments, tozorakimab or a pharmaceutical composition thereof is administered to a subject at a dose of 600 mg every 4 weeks (Q4W). In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject at a dose of 300 mg every 2 weeks (Q2W). In some embodiments, tozorakimab or a pharmaceutical composition thereof is administered to a subject at a dose of 300 mg every 2 weeks (Q2W).

[0229] When the administration interval is expressed in weeks, one week may include a tolerance that can be expressed as 7 days ± 1 day. In some embodiments, one week may be expressed as 7 days ± 0.5 days, 7 days ± 0.25 days, or exactly 7 days. If the administration interval is multiple weeks, the tolerances for each week may be summed. For example, in some embodiments, the administration interval is 4 weeks ± 4 days. In some embodiments, the administration interval is 4 weeks ± 3 days. In some embodiments, the administration interval is 4 weeks ± 2 days. In some embodiments, the administration interval is 4 weeks ± 1 day. In some embodiments, the administration interval is exactly 4 weeks. In some embodiments, the administration interval is 8 weeks ± 4 days. In some embodiments, the administration interval is 8 weeks ± 3 days. In some embodiments, the administration interval is 8 weeks ± 2 days. In some embodiments, the administration interval is 8 weeks ± 1 day. In some embodiments, the administration interval is exactly 8 weeks.

[0230] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered during a “treatment period,” the term as used herein refers to the period from the time of administration of the first dose until the administration of the final dose of tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof. The date on which the first dose is administered is referred to as “Day 1” or “Week 0,” and Week 1 begins 7 days thereafter, and Week 2 begins again 7 days thereafter, and so on. In some embodiments, the treatment period is 16 weeks in length (i.e., Week 0 through Week 15), and a total of 4 doses are administered with an interval of 4 weeks (Week 0, Week 4, Week 8, and Week 12, respectively). In some embodiments, the treatment period is 12 weeks long and the administration interval is 4 weeks, with doses administered on day 1 (week 0), day 29 ± 4 (week 4), day 57 ± 4 (week 8) and day 85 ± 4 (week 12).

[0231] In some embodiments, 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 embodiments, the treatment period is 52 weeks or more. In some embodiments, the treatment period is 48 weeks or more. In one embodiment, the treatment period is 24 weeks. In one embodiment, the treatment period is 24 weeks long, and the administration interval is 4 weeks.

[0232] Route of administration

[0233] A method of administering tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof to a subject in need thereof is well known to those skilled in the art or can be easily determined by those skilled in the art.

[0234] Appropriately, the route of administration of tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof may be parenteral. Appropriately, as used herein, the term “parenteral” includes, for example, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration.

[0235] Suitablely, parenteral formulations may be a single bolus dose, an infusion, or a loading bolus dose followed by a maintenance dose. These compositions may be administered at specific fixed or variable intervals, such as once a day, or on a "as needed" basis.

[0236] In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered subcutaneously to a subject. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject by injection. In some embodiments, tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject by subcutaneous injection.

[0237] The present disclosure will be described below with reference to the following drawings.

[0239] Figure 1 shows the results of tozorakimab 600 mg Q4W compared to placebo in a subgroup of moderate or severe asthma patients enrolled in the FRONTIER-3 study who experienced two or more exacerbations in the previous 12 months. Preparation This indicates that at week 16, the clinic BD significantly improved pre-FEV1 by 0.195 L (87.8 to 301.9) (statistical significance P value < 0.1).

[0240] Figure 2 shows that in a subgroup of moderate or severe asthma patients enrolled in the FRONTIER-3 study who experienced two or more exacerbations in the previous 12 months, tozorakimab 600 mg Q4W demonstrated higher efficacy compared to placebo in improvement of clinic-BD-FEV1 (statistical significance P < 0.1).

[0241] Figure 3 shows that in a subgroup of moderate or severe asthma patients enrolled in the FRONTIER-3 study who experienced two or more exacerbations in the previous 12 months, tozorakimab 600 mg Q4W demonstrated higher efficacy compared to placebo in home-measured FEV1 improvement (statistical significance P < 0.1).

[0242] Figure 4 shows that in a subgroup of moderate or severe asthma patients enrolled in the FRONTIER-3 study who experienced two or more exacerbations in the previous 12 months, tozorakimab 600 mg Q4W demonstrated higher efficacy compared to placebo in improving PEF (statistical significance P < 0.1).

[0243] Figure 5a shows that in the ITT (whole treatment cohort), tozorakimab demonstrated a similar effect compared to placebo on the self-measured FEV1 secondary endpoint in both subjects with a baseline EOS greater than 300 and less than 300.

[0244] Figure 5b shows that in the ITT (whole treatment cohort), tozorakimab demonstrated a similar effect compared to placebo on the PEF secondary endpoint in both subjects with a baseline EOS greater than 300 and less than 300.

[0245] Examples

[0246] Example 1 Phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MEDI3506 (tozorakimab) in adult participants with uncontrolled moderate to severe asthma

[0247] Research Design

[0248] This study was 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 (hereinafter referred to as "tozorakimab") in adult participants with uncontrolled moderate to severe asthma receiving standard of care (SoC). Participants who failed screening were eligible for re-screening.

[0249] Participants were centrally assigned to the randomization intervention using a randomization and trial supply management system to receive tozorakimab 600 mg, tozorakimab 300 mg, or placebo via subcutaneous (SC) injection every four weeks (Q4W) for a total of four doses over four weeks. Randomization was stratified based on participation in the cough substudy. Since tozorakimab and placebo are not identical, the trial intervention was managed by the institution's unblind trial intervention manager and administered by unblind trial team members who were not involved in participant management. Participants were required to maintain regular asthma control therapy throughout the screening, intervention, and follow-up periods.

[0250] Objectives and Evaluation Variables

[0251]

[0252] Target group and sample size

[0253] Eligibility was for adults (18 years of age or older but less than 65 years of age) with a history of being diagnosed by a physician with early-onset asthma, defined as the onset of asthma before age 25. Asthma had to be diagnosed at a time greater than 12 months prior to Study Visit 1 (SV1). Participants had to receive moderate to high-dose inhaled corticosteroid (ICS) treatment defined as fluticasone dry powder or equivalent doses exceeding 250 μg on a total daily basis for at least 12 months prior to SV1, maintain a stable dose for at least 3 months prior to SV1, and also receive stable long-acting beta-agonist treatment for at least 3 months prior to SV1 (this could be a fixed-dose combination or a separate inhaler). Additional asthma control treatments prior to SV1, such as long-acting muscarinic antagonists, leukotriene receptor antagonists, or theophylline (at a stable dose for at least 1 month), were also permitted. Participants had to have an Asthma Control Questionnaire-6 (ACQ-6) score of 1.5 or higher in each of SV1, SV2, and SV4 (randomized), and in SV1, an FEV1 (relative to predicted normal value) of less than 85% before morning bronchodilator administration (BD).

[0254] Approximately 228 participants were randomized in a 1:1:1 ratio (tozorakimab 600 mg : tozorakimab 300 mg : placebo) to secure 216 evaluable participants (72 per treatment group). The sample size of 216 participants provided a minimum power of 80% to detect a statistically significant difference in the change in BD-pre-FEV1 from baseline at week 16, assuming a difference of 150 mL between placebo and tozorakimab, a standard deviation (SD) of 420 mL between participants, and a one-sided 10% significance level.

[0255] Up to 60 participants were planned to be included in the cough sub-study (approximately 20 per treatment group). However, considering the exploratory nature of the sub-study and the possibility that it may not be active in some countries, the randomization of participants not included in the sub-study was not restricted, and recruitment for the sub-study was not achieved. The sub-study was considered an exploratory study, and formal power calculations were not performed.

[0256] Investigational drug and comparator: Dosage, method of administration

[0257] Tozorakimab was manufactured by AstraZeneca and supplied as a subcutaneous injectable solution contained in 1 mL vials. Tozorakimab was administered at doses of 300 mg and 600 mg every 4 weeks over a total of 4 doses. In the 300 mg group, participants received 2 mL of tozorakimab in a 1 × 2 mL syringe and 2 mL of placebo in a 1 × 2 mL syringe. In the 600 mg group, participants received 4 mL of tozorakimab in a 2 × 2 mL syringe. In the placebo group, participants received a placebo in a 2 × 2 mL syringe.

[0258] Treatment period

[0259] Participants will be enrolled in this study for up to 29 weeks. This study consists of three periods, including a screening period of up to 5 weeks, an intervention period of 16 weeks, and a follow-up period of 8 weeks.

[0260] Efficacy evaluation

[0261] spirometry (bronchodilation-before and bronchodilation-after)

[0262] PNV will be determined using the International Pulmonary Functioning System equations and pre-programmed into the spirometer. FEV1, expressed as a percentage of PNV, will be calculated as follows:

[0263] FEV1% of PNV = (Measured FEV1 / FEV1PNV) × 100

[0264] Bronchodilation can be induced using up to four inhalations of albuterol (90 μg metered dose), salbutamol (100 μg metered dose), or levalbuterol (45 μg metered dose). The use of a spacer device is strongly recommended for this procedure.

[0265] After a mild and complete exhalation, up to four inhalations of salbutamol (100 μg metered dose) or albuterol (90 μg metered dose) should be administered using a spacer device. In the rare case where the participant has an adverse or allergic reaction to albuterol / salbutamol, levalbuterol (45 μg metered dose, up to four inhalations) may be used (Sorkness et al 2008). Nebulizers must not be used. If there are concerns regarding any effect on the participant's safety, a lower total dose (e.g., two inhalations instead of four, and up to four puffs if necessary) may be used; the reason must be stated in the participant's medical record.

[0266] To determine reversibility, the technically acceptable highest FEV1 before and after BD will be used. Reversibility is calculated as follows:

[0267] FEV1% Reversibility = (BD - After FEV1 - BD - Before FEV1) / BD - Before FEV1 × 100

[0268] Self-recording of lung capacity

[0269] During the study period, participants are required to self-monitor their lung function twice a day using a self-monitoring spirometry device.

[0270] Fractional aerobic nitrogen oxide

[0271] Airway inflammation will be evaluated using a standardized single-exhalation FeNO test. The single-exhalation technique recommended by the manufacturer will be followed (References [Allakhverdi et al 2007]; References [Alving et al 2017]). The FeNO test will be performed prior to AO and spirometry measurements. Participants must comply with relevant medications and other restrictions prior to the evaluation (Sections 6.5.3 and 5.3). If any of the above restrictions are not met and the evaluation cannot be sufficiently delayed on the day, the evaluation must be rescheduled within an allowed visit period.

[0272] FeNO will be measured using the NIOX VERO® airway inflammation monitor. Instructions for using this monitor will be provided in a separate user manual. The NIOX VERO® sensor will be replaced as recommended by the manufacturer. The vendor supplying the equipment will be responsible for ensuring that the equipment and procedures for measuring FeNO have been verified prior to the start of the study.

[0273] Where possible, all post-randomization FeNO evaluations should be performed within ± 1.5 hours of the time of the FeNO evaluation performed at the time of randomization.

[0274] Asthma Control Questionnaire-6

[0275] 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 have confirmed that the primary clinical goal of asthma management is to optimize asthma control (minimizing symptoms, activity limitations, bronchoconstriction, and structural BD use) to reduce 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 occurring spontaneously or as a result of treatment.

[0276] In the ACQ-6, participants are asked to recall how their asthma was during the previous week by responding to one BD usage question and five symptom questions. Each item is assigned an equal weight and scored from 0 (fully controlled) to 6 (severely poorly controlled). The mean ACQ-6 score is the average of the responses. A mean score of 0.75 or lower indicates well-controlled asthma, a score between 0.75 and 1.5 indicates partially controlled asthma, and a score greater than 1.5 indicates poorly controlled asthma (Juniper et al 2006). An individual change of 0.5 or more is considered clinically significant.

[0277] St. George's Respiratory Questionnaire

[0278] The SGRQ is a 50-item PRO medium developed to measure the health status of participants with airway obstruction disease (Reference [Jones et al 1991]). The questionnaire is divided into two parts: Part 1 consists of 8 items regarding the severity of respiratory symptoms within the previous 4 weeks; and Part 2 consists of 42 items regarding the daily activities and psychosocial impact of the individual's respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activity, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of total impairment, where 100 represents the worst possible health status and 0 represents the best possible health status. Similarly, the domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details regarding the scoring algorithm are provided by the developers in the user manual (Reference [Jones and Forde 2009]).

[0279] Assessment and documentation of asthma exacerbations

[0280] During the study, asthma exacerbation will be defined as a change in a participant's general asthma symptoms leading to any of the following:

[0281] a. A transient bolus / burst of systemic corticosteroid for 3 consecutive days or more to treat symptoms of asthma exacerbation (or a transient increase of a stable OCS background dose); a single depot-injectable dose of corticosteroid will be considered equivalent to a 3-day bolus / burst of systemic corticosteroid.

[0282] b. Visit to an emergency room or urgent care center due to asthma requiring systemic corticosteroids (as above) (defined as evaluation and treatment for less than 24 hours at an emergency medicine or urgent care center).

[0283] c. Patient admission (defined as admission to an inpatient facility and / or evaluation and treatment for 24 hours or more at a healthcare facility).

[0284] An inpatient asthma exacerbation is defined as any exacerbation of asthma leading to (c.) above. Note: For each exacerbation, the criteria / standards met to confirm the exacerbation status must be documented.

[0285] The list below defines what constitutes acceptable documentation regarding past exacerbations, appropriately during the 12 months prior to treatment:

[0286] ㆍ A discharge summary from a hospital, emergency room, or urgent care facility indicating that the participant was admitted to / treated with systemic corticosteroids due to asthma exacerbation.

[0287] ㆍ A signed and dated memo from the referring physician containing information regarding the diagnosis and treatment of exacerbation using systemic corticosteroids.

[0288] ㆍ Evidence of prescription for systemic corticosteroids used during exacerbation.

[0289] ㆍ Documented conversations between a participant and a researcher (or agent) already on the OCS action plan, containing information necessary to evaluate Inclusion Criterion 19.

[0290] ㆍ Documented conversations between the treating / referring physician or nurse / clinical nurse proving that the participant was treated for exacerbations with corticosteroids at their clinic or under their supervision. The date (month / year) of the exacerbation and verbal confirmation that an appropriate prescription was provided are required. This option should be used only if reasonable attempts to obtain the subject's records have not been successful.

[0291] The following guidelines define the assessment of asthma exacerbation. The onset of an exacerbation is defined as the earliest of the following:

[0292] ㆍ Onset of systemic corticosteroids or transient increase in stable OCS background dose.

[0293] ㆍ Date of emergency room or urgent treatment visit requiring systemic corticosteroids.

[0294] Date of hospital admission due to asthma.

[0295] The end date of exacerbation is defined as the latest of the following:

[0296] Last date of systemic corticosteroids or transient increase in stable OCS background dose.

[0297] ㆍ Date of discharge from the emergency room or urgent treatment visit.

[0298] ㆍ Hospital discharge date.

[0299] If less than 7 days have passed since the end date of the asthma exacerbation and the start date of the new asthma exacerbation, the second event will be considered a recurrence of the preceding asthma exacerbation in statistical analysis.

[0300] All asthma exacerbations occurring during the treatment period and follow-up must be recorded in the exacerbation eCRF.

[0301] Daily eDiary

[0302] During the study period, participants will be asked to regularly receive their asthma control therapy and to fill out an electronic diary twice a day.

[0303] In SV1, participants will receive a portable electronic diary device to record bi-daily, daily, and non-daily PRO assessments during the study. Participants will be provided with training on the use of the portable device. Daily assessments will include nighttime and daytime asthma symptoms (morning and evening diaries, respectively), use of inhaled rescue medication in response to exacerbations, nights of awakening due to asthma symptoms (morning diary alone), and background medication use. PEF data (obtained from a home peak flow meter) will be captured at the completion of the morning and evening electronic diary entries.

[0304] Daytime is defined as the period between the morning lung function assessment (upon waking in the morning) and the evening lung function assessment. Nighttime is defined as the period between the evening lung function assessment (upon going to sleep) and the morning lung function assessment.

[0305] The number of doses of rescue medication received (one dose unit = one puff on the inhaler) will be recorded twice daily by the participant in an electronic log. The number of inhalations received between the morning and evening lung function assessments will be recorded in the evening.

[0306] The number of inhalations received between the evening and morning lung function assessments will be recorded in the morning.

[0307] Nocturnal awakenings due to asthma symptoms will be recorded in the daily electronic log every morning by the participant answering 'yes' or 'no' to the question of whether they were awakened by asthma symptoms during the night.

[0308] Background (inhaled ICS / LABA) drug administration use will be recorded once daily in the daily electronic log as a "yes" or "no" response.

[0309] CompEx

[0310] CompEx is a combination of asthma and exacerbations of diary events (i.e., a combination of electronic diary variables). CompEx is a composite surrogate endpoint for asthma exacerbations recently developed by AstraZeneca (it is not yet a regulatory-approved clinical endpoint). Diary events are defined by threshold and slope criteria using the following morning / evening (AM / PM) diary variables:

[0311] ㆍ PEF

[0312] Symptom score (0 to 3)

[0313] ㆍ Use of rescue drugs

[0314] CompEx can predict therapeutic efficacy against exacerbations in early development prior to running traditional long-term exacerbation trials. CompEx can be widely used to evaluate new therapeutic interventions for asthma (Reference [Fuhlbrigge et al 2017]; Note: Although the referenced publication used the term 'severe exacerbation,' it used the same definition as 'exacerbation' in this protocol; therefore, for internal consistency of the protocol, the term 'exacerbation' has been used in this section.)

[0315] Statistical analysis

[0316] Efficacy analysis was performed using the Intent-to-treat (ITT) group. The primary estimate was the following 'Treatment Policy' estimate: For the ITT group, the difference in mean change in BD-pre-FEV1 from baseline at Week 16 (tozorakimab - placebo) was to be estimated using a repeated measures mixed-effects ANOVA model. The primary estimate is as follows: This included all available data from all visits up to and including Week 16, regardless of whether the participant discontinued the study intervention or received rescue therapy.

[0317] A similar approach was applied to the analysis of ACQ-6, the St. George's Respiratory Questionnaire (SGRQ), and exhaled fractional nitric oxide (FeNO). The difference in mean change in FEV1 relative to baseline after BD at weeks 8 and 16 was to be estimated using a repeated-measures mixed-effects ANOVA model similar to that described for the primary efficacy analysis. Data may have been log-transformed prior to analysis where appropriate. The time to the first CompEx event and the time to the first asthma exacerbation will be analyzed using a Cox proportional hazards model fitted with treatment as a covariate.

[0318] Research subject group

[0319] Of the 478 screened patients, 235 participants were randomized in a 1:1:1 ratio at 52 study sites in 7 countries to receive placebo (81 participants), tozorakimab 300 mg (77 participants), or tozorakimab 600 mg (77 participants). At the end of the study, all participants had either completed treatment (225 participants [95.7%]) or discontinued it (10 participants [4.3%]). Overall, 227 participants (96.6%) completed the study.

[0320] Demographic and disease characteristics represented the intended population of adults with uncontrolled moderate to severe asthma, and were generally similar between the treatment groups, except that the proportion of female participants in the placebo group (53.1%) was lower than in the tozorakimab group (69.5%).

[0321] Validation Result Summary

[0322] Primary evaluation variable

[0323] Regarding the change in BD-pre-FEV1 from baseline measured at clinic at Week 16, the tozorakimab 300 mg group or the tozorakimab 600 mg group entireNo statistically significant difference compared to placebo was demonstrated for this (300 mg: Least Squares Mean (LSMean) difference [Tozorakimab - Placebo] 0.036 L [80% Confidence Interval (CI): -0.038, 0.111], p = 0.267; 600 mg: LSMean difference 0.004 L [80% CI: -0.071, 0.079], p = 0.473).

[0324] However, regarding clinic-measured BD-pre-FEV1 at week 16, a statistically significant improvement was observed in the tozorakimab 600 mg Q4W group in the subgroup of participants who had experienced two or more exacerbations in the 12 months prior to tozorakimab administration (see table below). In this group, tozorakimab 600 mg Q4W improved clinic FEV1 at week 16 by 0.195 L (87.8, 301.9) compared to placebo. This improvement was also reflected in the home BD-pre-FEV1 endpoint in the same participant group. In participants who had experienced two or more exacerbations in the 12 months prior to tozorakimab administration, a significant improvement of 95 mL (23.0, 167.6) in home-measured BD-pre-FEV1 was also observed in the tozorakimab 600 mg Q4W group compared to placebo at week 16.

[0325]

[0326] Secondary evaluation variable

[0327] In terms of BD-post-FEV1 measured at the clinic, no statistically significant difference was observed between the tozorakimab 300 mg group and the 600 mg group and the placebo at week 8 or week 16.

[0328] In terms of the change in ACQ-6 score from baseline at week 16, no statistically significant difference was observed between the tozorakimab 300 mg or 600 mg groups and the placebo group.

[0329] Compared to the placebo group, the proportion of participants whose ACQ-6 score decreased by 0.5 or more at week 16 from baseline was numerically higher in both the tozorakimab 300 mg and tozorakimab 600 mg groups, but the difference between groups regarding the proportion of responders was not clinically significant.

[0330] Compared to the placebo group, there was no statistically significant difference in the proportion of participants who achieved a well-controlled ACQ-6 score in the tozorakimab 300 mg or tozorakimab 600 mg groups at week 16.

[0331] No statistically significant difference was observed between the tozorakimab 300 mg or 600 mg groups and the placebo group in the change from baseline of the SGRQ area score and total score at week 16.

[0332] Compared to the placebo group, there was no statistically significant difference in the proportion of participants whose total SGRQ score decreased by 4 points or more at week 16 from baseline between the tozorakimab 300 mg group and the tozorakimab 600 mg group.

[0333] ㆍ In terms of time to the first CompEx event based on the period from baseline to week 16, there was no statistically significant difference between the placebo group and either the tozorakimab 300 mg group or the tozorakimab 600 mg group.

[0334] The annual event rate of CompEx up to week 16 was numerically lower in the tozorakimab 600 mg group (0.69) than in the tozorakimab 300 mg group (0.86) or the placebo group (0.99), but the difference between each tozorakimab group and the placebo group was not statistically significant.

[0335] However, in the group of participants who received tozorakimab 600 mg Q4W and experienced two or more exacerbations in the 12 months prior to tozorakimab administration, other endpoints were found to be improved: in this group, PEF (AM / PM) was significantly improved by 9.212 L / min (0.071, 18.352) at week 16 compared to placebo.

[0336] conclusion

[0337] This study did not meet its primary objective. Regarding the change from baseline to BD-pre-baseline measured at clinic-administered at Week 16 in the ITT group, the tozorakimab 300 mg group or the tozorakimab 600 mg group entire No statistically significant or clinically meaningful difference compared to placebo was demonstrated.

[0338] However, this study met other endpoints in a specific population. In a subgroup of participants, significant improvement was achieved in pre-BD FEV1 at week 16 as measured at the clinic. This participant subgroup received tozorakimab 600 mg Q4W and consisted of participants who had experienced two or more exacerbations during the 12 months prior to tozorakimab administration.

[0339] order

[0340] In addition to the sequences listed in Table 1, the following additional sequences are provided:

[0341] MEDI3506 VHCDR1 Sequence No. 37: SYAMS

[0342] MEDI3506 VHCDR2 Sequence No. 38: GISAIDQSTYYADSVKG

[0343] MEDI3506 VHCDR3 Sequence No. 39: QKFMQLWGGGLRYPFGY

[0344] MEDI3506 VLCDR1 Sequence No. 40: SGEGMGDKYAA

[0345] MEDI3506 VLCDR2 서열번호 41: RDTKRPS

[0346] MEDI3506 VLCDR3 서열번호 42: GVIQDNTGV

[0347] 서열 번호:43 MEDI3506 중쇄

[0348] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0349] 서열 번호:44 MEDI3506 경쇄

[0350] SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

Claims

Claim 1 A method for treating a subject with moderate or severe asthma, the method comprising the step of administering an effective amount of tozorakimab to the subject, wherein the subject has experienced two or more asthma exacerbations during the 12 months prior to the administration. Claim 2 A method for improving lung function in a subject with moderate or severe asthma, the method comprising the step of administering an effective amount of tozorakimab to the subject, wherein the subject has experienced two or more asthma exacerbations during the 12 months prior to the administration. Claim 3 A method for increasing the BD-pre-FEV1 of a subject with moderate or severe asthma by at least 100 ml, the method comprising the step of administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject has experienced two or more asthma exacerbations during the 12 months prior to the administration. Claim 4 A method for treating moderate or severe asthma in a subject by increasing the subject's BD-pre-FEV1 by at least 100 ml in paragraph 3. Claim 5 A method according to any one of claims 1 to 4, wherein the subject has a blood eosinophil count of less than 300 cells / μl prior to administration. Claim 6 In paragraph 5, the method wherein the subject is selected from a group of subjects including the number of eosinophils in the blood prior to the administration. Claim 7 A method according to claim 5 or 6, further comprising the step of selecting a subject having the blood eosinophil count prior to the administration. Claim 8 A method in which, in any one of paragraphs 1 or 5 through 7, the treatment of a subject having moderate or severe asthma results in an improvement in the subject's lung function. Claim 9 A method according to any one of claims 1 to 8, wherein the treatment of a subject with moderate or severe asthma, or the improvement of lung function of a subject with moderate or severe asthma, or the increase in FEV1 prior to administration of a bronchodilator (BD) of a subject with moderate or severe asthma, is a method of increasing the FEV1 of the subject prior to administration of a bronchodilator (BD) by at least 100 ml, 105 ml, 110 ml, 115 ml, 120 ml, 125 ml, 130 ml, 135 ml, 140 ml, 145 ml, 150 ml, 155 ml, 160 ml, 165 ml, 170 ml, 175 ml, 180 ml, 185 ml, 190 ml, 195 ml, or at least 200 ml, optionally about 200 ml. Claim 10 A method according to any one of claims 1 to 9, wherein the treatment of a subject with moderate or severe asthma, or the improvement of lung function of a subject with moderate or severe asthma, or the increase in BD-pre-FEV1 of a subject with moderate or severe asthma, further increases the subject's peak expiratory flow rate (PEF) by at least 5 L / min, at least 5.5 L / min, at least 6 L / min, at least 6.5 L / min, at least 7 L / min, at least 7.5 L / min, at least 8 L / min, at least 8.5 L / min, or at least 9 L / min, optionally about 9 L / min. Claim 11 A method according to claim 9 or 10, wherein the increase in BD-pre-FEV1 or PEF of the subject is achieved by 16 weeks after administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. Claim 12 A method according to any one of claims 9 to 11, wherein the increase in BD-pre-FEV1 or PEF of the subject is achieved by 24 weeks after administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. Claim 13 A method according to any one of claims 1 to 12, wherein the treatment of a subject with moderate or severe asthma, or the improvement of lung function of a subject with moderate or severe asthma, or the increase in BD-pre-FEV1 of a subject with moderate or severe asthma, reduces the asthma exacerbation rate in the subject. Claim 14 A method according to claim 13, wherein the asthma exacerbation rate is reduced by at least 20%, at least 25%, at least 30%, optionally about 30% compared to a control subject with moderate or severe asthma who did not receive tozorakimab or an IL-33 signaling axis antagonist after administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. Claim 15 In paragraph 13 or 14, a method in which the asthma exacerbation rate is reduced over a period of 24 weeks. Claim 16 A method according to any one of paragraphs 1 to 15, wherein the subject has early-onset asthma. Claim 17 A method in any one of paragraphs 1 through 16, wherein the asthma is severe asthma. Claim 18 A method for selecting a subject for treatment with an effective amount of tozorakimab for a subject with moderate or severe asthma, comprising: a step of determining the number of asthma exacerbations experienced by the subject over the past 12 months; and a step of selecting the subject for said treatment if the subject has experienced more than 2 asthma exacerbations over the past 12 months. Claim 19 In claim 18, the method further comprises the step of selecting the subject for treatment when the number of eosinophils in the blood of the subject is less than 300 cells / μl. Claim 20 A method according to claim 18 or 19, wherein the method further comprises the step of administering an effective amount of tozorakimab to a subject. Claim 21 A method according to any one of claims 9 to 15, wherein the increase in FEV1, the increase in PEF, and the decrease in asthma exacerbation rate of the subject prior to bronchodilator administration (BD) are based on baseline levels. Claim 22 In paragraph 21, the baseline is the level of the subject prior to administration of an effective dose of tozorakimab or an IL-33 signaling axis antagonist. Claim 23 A method according to any one of paragraphs 3 to 22, wherein the IL-33 signaling axis antagonist is an antibody, an antigen-binding fragment, or a variant thereof. Claim 24 In paragraph 23, the antibody is an anti-IL-33 antibody, an anti-ST2 antibody, an anti-IL1-RacP antibody, an antigen-binding fragment, or a variant thereof. Claim 25 In paragraph 23 or 24, the antibody is an anti-IL-33 antibody, an antigen-binding fragment, or a variant thereof. Claim 26 A method according to any one of claims 23 to 25, wherein the anti-IL-33 antibody, antigen-binding fragment, or variant thereof comprises a VH domain comprising VHCDR1 having the sequence described in SEQ ID NO. 37, VHCDR2 having the sequence described in SEQ ID NO. 38, and VHCDR3 having the sequence described in SEQ ID NO. 39, and a VL domain comprising VLCDR1 having the sequence described in SEQ ID NO. 40, VLCDR2 having the sequence described in SEQ ID NO. 41, and VLCDR3 having the sequence described in SEQ ID NO.

42. Claim 27 A method according to any one of claims 23 to 26, wherein the anti-IL-33 antibody, antigen-binding fragment, or variant thereof comprises a VH domain having a sequence described in SEQ ID NO. 1 or a sequence 80%, 85%, 90%, or 95% identical thereto, and a VL domain having a sequence described in SEQ ID NO. 19 or a sequence 80%, 85%, 90%, or 95% identical thereto. Claim 28 A method according to any one of claims 23 to 27, wherein the anti-IL-33 antibody, antigen-binding fragment, or variant thereof comprises a heavy chain having the sequence described in SEQ ID NO. 43 or a sequence 80%, 85%, 90%, or 95% identical thereto, and a light chain having the sequence described in SEQ ID NO. 44 or a sequence 80%, 85%, 90%, or 95% identical thereto. Claim 29 A method in which, in any one of paragraphs 23 to 28, the antibody is tozorakimab. Claim 30 A method according to any one of claims 1 to 29, wherein an effective amount of tozorakimab or an IL-33 signaling axis antagonist is contained in a pharmaceutical composition comprising one or more excipients. Claim 31 A method according to any one of claims 1 to 30, wherein the effective amount of tozorakimab or IL-33 signaling axis antagonist is a dose in the range of 300 mg to 600 mg. Claim 32 A method according to any one of claims 1 to 31, wherein tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject every 2 weeks (Q2W), every 4 weeks (Q4W), or every 8 weeks (Q8W). Claim 33 A method according to any one of claims 1 to 32, wherein tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject at a dose of 600 mg every 4 weeks (Q4W). Claim 34 A method according to any one of claims 1 to 33, wherein tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject at a dose of 300 mg every 2 weeks (Q2W). Claim 35 A method according to any one of claims 1 to 34, wherein tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered subcutaneously to a subject. Claim 36 A method according to any one of claims 1 to 35, wherein tozorakimab or an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to a subject by injection.

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