RU2840902C2 - Methods of normalizing asthma symptoms using benralizumab - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology and allergology, and can be used for treating asthma. Patient is administered from approximately 2 mg to approximately 100 mg of benralizumab or its antigen-binding fragment. Effectiveness of the treatment of asthma is determined by improving the score according to the asthma assessment questionnaire in a patient with asthma, where the asthma assessment questionnaire is selected from a group consisting of an asthma control questionnaire (ACQ), asthma control questionnaire-6 (ACQ-6) and a questionnaire for assessing quality of life in patients with asthma (AQLQ). According to the questionnaire, at least one symptom selected from the group consisting of: night awakening, symptoms upon awakening, limitation of activity, shortness of breath, wheezing, use of the emergency drug preparation, frequency and severity of symptoms in the daytime, frequency and severity of symptoms at night, avoidance of activity and its limitation, asthma-related anxiety and fatigue. Benralizumab or its antigen-binding fragment can be administered from once every four weeks to once every twelve weeks from approximately 2 mg to approximately 100 mg per dose.

EFFECT: method enables treating asthma by administering benralizumab or an antigen-binding fragment thereof to a patient with asthma and determining the effectiveness of treating asthma by improving the score according to the patient’s asthma assessment questionnaire.

11 cl, 10 dwg, 4 tbl, 3 ex

Description

Link to sequence listing

[0001] This application contains a sequence listing that was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 16, 2014, is named IL5R-605WO1_SL.txt and is 15940 bytes in size.

PREREQUISITES

[0002] More than 300 million people worldwide suffer from asthma. Despite the use of long-acting bronchodilators and inhaled corticosteroids, asthma remains a major source of morbidity worldwide. (Masoli M, et al. Allergy 59: 469-78(2004)).

[0003] Following an acute asthma attack, relapse has been reported in 41-52% of cases within 12 weeks despite the use of systemic steroids after discharge (Lederle F et al. Arch Int Med 147: 2201-03 (1987)). Management of these patients has proven problematic due to either severe refractory disease or inability and/or unwillingness to comply with pharmacotherapy. In one study of hospitalized patients, some with near-fatal asthma, 50% of patients were noncompliant with systemic corticosteroids 7 days after discharge (Krishnan J et al. AJRCCM 170: 1281-85 (2004)). Many factors can contribute to non-adherence, including poor access to quality health care (especially in low-income areas of the city), lack of education or understanding of one's disease, reluctance to acknowledge the chronic nature of one's disease, or lack of access to medications.

[0004] Based on multiple data sets, eosinophils are the major cells that cause airway inflammation in asthma (James A. Curr Opin Pulm Med 11 (1): 1-6 (2005)). Peripheral blood (PB) eosinophilia is a risk factor for relapse of acute asthma (Janson C and Herala M. Resp Med 86 (2): 101-104 (1992)). Subjects with PB eosinophilia have a 7.4-fold (confidence interval, 2.8-19.7) greater risk of dying from asthma than subjects without eosinophilia (Ulrik C and Fredericksen J. Chest 108: 10-15 (1995)). Autopsy findings have identified 2 distinct mechanisms of inflammation in fatal asthma (Restrepo R and Peters J. Curr Opin Pulm Med 14: 13–23 (2008)). Neutrophilic infiltrates are more prominent in people who die suddenly (within approximately 2 hours of symptom onset), while eosinophilic infiltrates are more prevalent in people who die from more prolonged asthmatic crises. Patients with rapid onset of asthma symptoms presenting to the emergency department may also have increased sputum and blood eosinophil counts (Bellido-Casado J. et al. Arch Bronconeumol 46 (11): 587–93 (2010)). Therapies that target eosinophils result in a reduction in the number and severity of asthma attacks compared with clinical guidelines (Green R. et al. Lancet 360: 1715-21 (2002); Haldar P. et al. NEJM 360: 973-84 (2009)).

[0005] Benralizumab (MEDI-563) is a humanized monoclonal antibody (mAb) that binds to the alpha chain of the interleukin-5 receptor alpha (IL-5Rα), which is expressed on eosinophils and basophils. It induces apoptosis of these cells through antibody-dependent cellular cytotoxicity. A single intravenous (IV) dose of benralizumab administered to adults with mild asthma caused prolonged PB eosinopenia, likely due to effects on bone marrow eosinophil/basophil progenitor cells that express the target (Busse W. et al. JACI 125: 1237–1244 e2 (2010)). In addition, a single dose of benralizumab significantly reduced blood eosinophil counts in subjects admitted to the emergency department with a severe asthma attack, but had no effect on the Asthma Control Questionnaire (ACQ) score, which assesses asthma symptoms (WO 2013/066780).

[0006] The ACQ is a patient-reported questionnaire assessing asthma symptoms (night awakening, symptoms on awakening, activity limitation, dyspnea, wheezing) and daily use of rescue bronchodilators and forced expiratory volume in one second (FEV ₁ ) Juniper et al. Eur. Respir. J. 14: 902–7 (1999) and Juniper et al. Chest 115:1265–70 (1999). Questions are equally weighted and are assigned a score from 0 (complete control) to 6 (very poor control). The mean ACQ score is the average of responses. Mean scores ≤0.75 are indicative of well-controlled asthma; scores 0.75 to ≤1.5 are indicative of partially controlled asthma; and scores >1.5 are indicative of uncontrolled asthma. Juniper et al. Respir. Med. 100: 616–21 (2006). Individual changes of at least 0.5 are considered clinically significant. Juniper et al. Respir. Med. 99: 553–8 (2005). The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night awakening, symptoms on awakening, activity limitation, dyspnea, wheezing, and rapid-acting β2 agonist use) by excluding the FEV ₁ measurement from the original ACQ score. Other questionnaires such as the Asthma Treatment Assessment Questionnaire (ATAQ), the Asthma Control Test (ACT), the Asthma Quality of Life Questionnaire (AQLQ), and asthma diaries can also be used to assess asthma symptoms.

[0007] Thus, given the large unmet need to improve asthma symptoms, such as those measured using the ACQ, and that some patients with asthma have an eosinophilic component, the effect of benralizumab on asthma-related questionnaires was investigated in adult subjects.

BRIEF DESCRIPTION

[0008] Provided herein are methods for improving an asthma questionnaire score in a patient with asthma. In certain aspects, a method for improving an asthma questionnaire score in a patient with asthma comprises administering to the patient an effective amount of benralizumab or an antigen-binding fragment thereof. In certain aspects, the questionnaire assesses at least one symptom selected from the group consisting of night awakening, symptoms on awakening, activity limitation, shortness of breath, wheezing, rescue medication use, daytime symptom frequency and severity, nighttime symptom frequency and severity, activity avoidance and limitation, asthma-related anxiety, and fatigue. In certain aspects, the questionnaire assesses night awakening, symptoms on awakening, activity limitation, shortness of breath, wheezing, and rescue medication use. In certain aspects, the questionnaire assesses daytime symptom frequency, daytime symptom severity, and nighttime severity. In some aspects, the questionnaire is the Asthma Control Questionnaire (ACQ). In some aspects, the Asthma Assessment Questionnaire is the Asthma Control Questionnaire-6 (ACQ-6). In some aspects, the Asthma Assessment Questionnaire is the Asthma Quality of Life Questionnaire (AQLQ).

[0009] Also provided herein are methods for treating asthma. In certain aspects, a method for treating asthma comprises administering to a patient with asthma an effective amount of an antibody to the interleukin-5 receptor (IL-5R), benralizumab, or an antigen-binding fragment thereof, wherein the patient's blood eosinophil count prior to administration is at least 300 cells/μl.

[0010] In certain aspects, a method of treating asthma comprises administering to a patient with asthma an effective amount of benralizumab or an antigen-binding fragment thereof, wherein the patient's forced expiratory volume in one second (FEV ₁ ) prior to administration is at least 75% of the predicted value.

[0011] In certain aspects, a method of treating asthma comprises administering to a patient with asthma at least two doses of benralizumab or an antigen-binding fragment thereof.

[0012] In certain aspects of the methods provided herein, the administration normalizes an asthma symptom in a patient. In certain aspects, the asthma symptom is selected from the group consisting of nighttime awakening, symptoms upon awakening, activity limitation, shortness of breath, wheezing, use of a rescue medication, daytime symptom frequency and severity, nighttime symptom frequency and severity, activity avoidance and limitation, asthma-related anxiety, and fatigue.

[0013] In certain aspects of the methods provided herein, the patient's ACQ score is reduced. In certain aspects, the patient's ACQ-6 score is reduced. In certain aspects, the patient's ACQ-6 score is reduced no later than 7 weeks after the first administration. In certain aspects, the ACQ-6 score is reduced by at least 0.5. In certain aspects, the ACQ-6 score is reduced by at least 1. In certain aspects, the ACQ-6 score is reduced by at least 2.

[0014] In certain aspects of the methods provided herein, the asthma is eosinophilic asthma. In certain aspects, the patient's blood eosinophil count is at least 300 cells/μL.

[0015] In certain aspects of the methods provided herein, the patient's forced expiratory volume in one second (FEV ₁ ) prior to administration is at least 75% of the predicted value. In certain aspects, the patient is using high-dose inhaled corticosteroids (ICS). In certain aspects, the patient's asthma control questionnaire score prior to administration is at least 1.5. In certain aspects, the patient is using long-acting β2 agonists (LABA). In certain aspects, the patient has a history of attacks. In certain aspects, the history of attacks includes at least two attacks in the year prior to administration of benralizumab or an antigen-binding fragment thereof. In certain aspects, the history of attacks includes no more than six attacks in the year prior to administration of benralizumab or an antigen-binding fragment thereof.

[0016] In certain aspects of the methods provided herein, the patient is administered at least two doses of benralizumab or an antigen-binding fragment thereof.

[0017] In certain aspects of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered at about 2 mg to about 100 mg per dose. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered at about 20 mg per dose. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered at about 30 mg per dose. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered at about 100 mg per dose.

[0018] In certain aspects of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered from once every four weeks to once every twelve weeks. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered once every four weeks. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered once every eight weeks. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered once every four weeks for twelve weeks, and then once every eight weeks.

[0019] In certain aspects of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered parenterally. In certain aspects, benralizumab or an antigen-binding fragment thereof is administered subcutaneously.

[0020] In certain aspects of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered in addition to corticosteroid therapy.

[0021] In certain aspects, a method for improving an asthma questionnaire score in a patient with asthma comprises administering to the patient with asthma 20-100 mg of benralizumab or an antigen-binding fragment thereof, wherein the patient's blood eosinophil count prior to administration is at least 300 cells/μL. In certain aspects, the method comprises administering 20 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, 20 mg of benralizumab is administered once every four weeks for twelve weeks and then once every eight weeks. In certain aspects, the method comprises administering 30 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, 30 mg of benralizumab is administered once every four weeks for eight weeks and then once every eight weeks. In certain aspects, 30 mg of benralizumab is administered once every four weeks. In certain aspects, the method comprises administering 100 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, 100 mg of benralizumab is administered once every four weeks for twelve weeks, and then once every eight weeks.

[0022] In certain aspects, a method of treating asthma in a patient with asthma comprises administering to the patient a dose of at least 2 mg and less than 100 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, the method comprises administering 20 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, the method comprises administering 30 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, the method comprises administering a dose of at least 20 mg and less than 100 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, the method comprises administering a dose of at least 30 mg and less than 100 mg of benralizumab or an antigen-binding fragment thereof. In certain aspects, the method reduces the frequency of asthma attacks. In certain aspects, the method reduces the annual frequency of asthma attacks. In certain aspects, the administration is subcutaneous.

[0023] In certain aspects of the provided methods, administration of benralizumab or an antigen-binding fragment thereof results in normalization of asthma symptoms, as shown in Figs. 2-10.

[0024] In certain aspects of the provided methods, administration of benralizumab or an antigen-binding fragment thereof results in normalization of asthma symptoms, as shown in Examples 1-2.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS/FIGURES

[0025] Fig. 1 shows a block diagram of the study.

[0026] Figure 2 shows the change from baseline in ACQ-6 at 24 weeks after initiation of treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients with less than 300 eosinophils/μL and patients with at least 300 eosinophils/μL.

[0027] Figure 3 shows the midterm (24 weeks) and stage I (52 weeks) change from baseline in ACQ-6 after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients with less than 300 eosinophils/μL and patients with at least 300 eosinophils/μL.

[0028] Figure 4 shows the midterm (24 weeks) and stage I (52 weeks) change from baseline in ACQ-6 after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients with moderate to high inhaled corticosteroid (ICS) use.

[0029] Figure 5 shows the midterm (24 weeks) and stage I (52 weeks) change from baseline in ACQ-6 after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients with less than 300 eosinophils/μL and (i) moderate ICS use or (ii) high ICS use.

[0030] Figure 6 shows the midterm (24 weeks) and stage I (52 weeks) change from baseline in ACQ-6 after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients with at least 300 eosinophils/μL and (i) moderate ICS use or (ii) high ICS use.

[0031] Figs. 7A and 7B show changes from baseline in ACQ-6 in patients with different eosinophil counts.

[0032] Fig. 8 shows the change in mean ACQ-6 score over time in patients with at least 300 eosinophils/μL.

[0033] Fig. 9 shows the change in mean diary total symptom score over time in patients with at least 300 eosinophils/μL.

[0034] Fig. 10 shows the mean change in AQLQ in patients with at least 300 eosinophils/μL.

DETAILED DESCRIPTION

[0035] It should be noted that the singular form of an object refers to one or more such objects; for example, it is intended that "an antibody to IL-5α" is one or more antibodies to IL-5α. In this regard, the singular forms, the expressions "one or more" and "at least one" may be used interchangeably herein.

[0036] This document provides methods for normalizing asthma symptoms, such as those assessed using an asthma questionnaire, such as the Asthma Control Questionnaire (ACQ), ACQ-6, Asthma Treatment Assessment Questionnaire (ATAQ), Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), or an asthma symptom diary. A symptom may be, for example, night awakening, symptoms on awakening, activity limitation, shortness of breath, wheezing, and/or rescue medication use (e.g., bronchodilator). A symptom may also be, for example, daytime symptom frequency and severity, nighttime symptom frequency and severity, activity avoidance and limitation, asthma-related anxiety, fatigue, and/or rescue medication use. Symptoms may also represent, for example, daytime symptom frequency, daytime symptom severity, and/or nighttime symptom severity. Provided methods include administering an effective amount of benralizumab or an antigen-binding fragment thereof.

[0037] Information regarding benralizumab (or fragments thereof) for use in the methods provided herein can be found in U.S. Patent Application Publication No. US 2010/0291073 A1, the disclosure of which is incorporated herein by reference in its entirety. Benralizumab and antigen-binding fragments thereof for use in the methods provided herein comprise a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In a further aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises any of the amino acid sequences of SEQ ID NOs: 1-4. In a particular aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3. In a particular aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:2 and a heavy chain comprising the amino acid sequence of SEQ ID NO:4. In a particular aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7-9, and wherein the light chain variable region comprises the Kabat defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 10-12. Those skilled in the art will readily recognize the Chothia defined, Abm defined, or other CDRs. In a particular aspect, benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the antibody KM1259 disclosed in U.S. Pat. No. 6,018,032, which is incorporated herein by reference in its entirety.

[0038] In certain aspects, benralizumab or an antigen-binding fragment thereof is administered to a patient presenting to a physician's office or emergency department with asthma. Given the ability of benralizumab to reduce or decrease eosinophil counts for up to 12 weeks or more ( see US 2010/0291073), benralizumab or an antigen-binding fragment thereof can be administered only once or infrequently and still provide benefit to the patient by improving ACQ and/or ACQ-6. In additional aspects, additional subsequent doses are administered to the patient. Subsequent doses may be administered at various intervals depending on the patient's age, weight, ability to comply with physician's orders, clinical examination, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) value, eosinophil neurotoxin (EDN) value, major basic protein (MBP) value and other factors, including the physician's judgment. Intervals between doses may be after four weeks, after five weeks, after 6 weeks, after 8 weeks, after 10 weeks, after 12 weeks or longer intervals. In certain aspects, intervals between doses may be after 4 weeks, after 8 weeks or after 12 weeks. In certain aspects, a patient with asthma is administered a single dose or the first dose immediately after the patient presents with an acute attack, such as a mild, moderate or severe attack. For example, a single or first dose of benralizumab or its antigen-binding fragment may be administered at the time of admission to the outpatient clinic or hospital or, in the case of very severe attacks, no later than 1, 2, 3, 4, 5, 6, 7 or more days, for example, 7 days after the acute attack, allowing the patient's symptoms to stabilize before administration of benralizumab.

[0039] In some embodiments, the patient is administered at least two doses of benralizumab or an antigen-binding fragment thereof. In some embodiments, the patient is administered at least three doses, at least four doses, at least five doses, at least six doses, or at least seven doses. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered for four weeks, for eight weeks, for twelve weeks, for twenty-four weeks, or for a year.

[0040] The amount of benralizumab or its antigen-binding fragment to be administered to a patient will depend on various parameters, such as the patient's age, weight, clinical parameters, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) level, eosinophil neurotoxin (EDN) level, major basic protein (MBP) level and other factors, including the judgment of the treating physician. In certain respects, the dosage or dosing interval is not affected by the sputum eosinophil level.

[0041] In certain aspects, the patient is administered one or more doses of benralizumab or an antigen-binding fragment thereof, wherein the dose is from about 2 mg to about 100 mg, such as from about 20 mg to about 100 mg or from about 30 mg to about 100 mg. In certain specific aspects, the patient is administered one or more doses of benralizumab or an antigen-binding fragment thereof, wherein the dose is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the dose is about 20 mg. In some embodiments, the dose is about 30 mg. In some embodiments, the dose is about 100 mg.

[0042] In certain aspects, administration of benralizumab or an antigen-binding fragment thereof according to the methods provided herein is via parenteral administration. For example, benralizumab or an antigen-binding fragment thereof can be administered by intravenous infusion or by subcutaneous injection.

[0043] In certain aspects, benralizumab or an antigen-binding fragment thereof is administered according to the methods provided herein in combination or in conjunction with additional asthma therapies. Such therapies include, but are not limited to, inhaled corticosteroid therapy, long-acting or short-acting bronchodilator therapy, oxygen administration, or other standard therapies as described, for example, in the NAEPP guidelines. In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof to a patient with asthma with a history of acute attacks, serves as adjunctive therapy in situations of poor compliance with standard asthma management.

[0044] The methods provided herein can significantly reduce ACQ or ACQ-6 scores in patients with asthma. The change in ACQ or ACQ-6 can be measured in comparison to an expected ACQ or ACQ-6 based on a large patient population, an ACQ or ACQ-6 measured in a control population, or an individual patient's ACQ or ACQ-6 before administration. In certain aspects, the patient population is patients who have had ≥2 attacks requiring oral systemic corticosteroids in the past year. In certain aspects, the patient population is patients who have had ≥2 attacks requiring pulse systemic corticosteroids in the past year and ≤6 attacks requiring pulse systemic corticosteroids in the past year. In certain aspects, the patient population is patients who have an eosinophil count of at least 300 cells/μL.

[0045] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves the ACQ or ACQ-6 scores over a period of 24 weeks following administration of benralizumab or an antigen-binding fragment thereof, compared to the patient's baseline ACQ or ACQ-6. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's orders, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. Application of the methods provided herein may reduce ACQ or ACQ-6 scores by at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, or at least 3.0 over a 24-week period.

[0046] In other aspects, the use of the methods provided herein, i.e., administering benralizumab or an antigen-binding fragment thereof to a patient with asthma, improves the ACQ or ACQ-6 scores over a period of 52 weeks following administration of benralizumab or an antigen-binding fragment thereof. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's orders, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. In certain aspects, the interval is after 4 weeks, after 8 weeks, or after 12 weeks. Application of the methods provided herein may reduce ACQ or ACQ-6 scores by at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, or at least 3.0.

[0047] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces ACQ or ACQ-6 scores no later than 4 weeks, no later than 7 weeks, no later than 8 weeks, no later than 9 weeks, no later than 10 weeks, no later than 12 weeks, no later than 16 weeks, no later than 20 weeks, no later than 24 weeks, no later than 28 weeks, no later than 32 weeks, no later than 36 weeks, no later than 40 weeks, no later than 44 weeks, no later than 48 weeks, or no later than 52 weeks.

[0048] The methods provided herein can also significantly improve asthma symptom diary scores that measure daytime symptom frequency, daytime symptom severity, and nighttime symptom severity. The change in such diary symptom scores can be measured in comparison to an expected diary symptom score based on a large patient population, a diary symptom score measured in a control population, or an individual patient's diary symptom score before administration. In certain aspects, the patient population is patients who have had ≥2 attacks requiring oral systemic corticosteroids in the past year. In certain aspects, the patient population is patients who have had ≥2 attacks requiring pulse systemic corticosteroids in the past year and ≤6 attacks requiring pulse systemic corticosteroids in the past year. In certain aspects, the patient population is defined as patients whose eosinophil count is at least 300 cells/μL.

[0049] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves the patient's diary symptom scores over a period of 24 weeks following administration of benralizumab or an antigen-binding fragment thereof compared to the patient's baseline diary symptom score. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's instructions, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. Use of the interventions described in this document can reduce diary symptom scores by at least 0.5 over a 24-week period.

[0050] In other aspects, the use of the methods provided herein, i.e., administering benralizumab or an antigen-binding fragment thereof to a patient with asthma, improves symptom scores according to a diary for a period of 52 weeks after administration of benralizumab or an antigen-binding fragment thereof. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's instructions, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. In certain aspects, the interval is after 4 weeks, after 8 weeks, or after 12 weeks. The use of the methods provided in this document can reduce the symptom scores according to the diary by at least 0.5.

[0051] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, reduces diary symptom scores no later than 4 weeks, 5 weeks, no later than 6 weeks, no later than 7 weeks, no later than 8 weeks, no later than 9 weeks, no later than 10 weeks, no later than 12 weeks, no later than 16 weeks, no later than 20 weeks, no later than 24 weeks, no later than 28 weeks, no later than 32 weeks, no later than 36 weeks, no later than 40 weeks, no later than 44 weeks, no later than 48 weeks, or no later than 52 weeks.

[0052] The methods provided herein can significantly increase AQLQ scores in patients with asthma. The change in AQLQ can be measured in comparison to an expected AQLQ based on a large patient population, an AQLQ measured in a control population, or an individual patient's AQLQ prior to administration. In certain aspects, the patient population is patients who have had ≥2 attacks requiring oral systemic corticosteroids in the past year. In certain aspects, the patient population is patients who have had ≥2 attacks requiring pulse systemic corticosteroids in the past year and ≤6 attacks requiring pulse systemic corticosteroids in the past year. In certain aspects, the patient population is patients who have an eosinophil count of at least 300 cells/μL.

[0053] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves the AQLQ score over a period of 24 weeks following administration of benralizumab or an antigen-binding fragment thereof compared to the patient's baseline AQLQ. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's orders, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. Application of the methods provided herein may increase AQLQ scores by at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, or at least 1.3 over a 24-week period.

[0054] In other aspects, the use of the methods provided herein, i.e., administering benralizumab or an antigen-binding fragment thereof to a patient with asthma, improves the AQLQ scores over a period of 52 weeks following administration of benralizumab or an antigen-binding fragment thereof. In certain aspects, the patient may receive subsequent doses of benralizumab or an antigen-binding fragment thereof at periodic intervals, such as at 4 weeks, at 5 weeks, at 6 weeks, at 8 weeks, at 12 weeks, or according to a schedule based on the patient's age, weight, ability to comply with physician's orders, clinical tests, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) score, eosinophil neurotoxin (EDN) score, major basic protein (MBP) score, and other factors, including the judgment of the treating physician. In certain aspects, the interval is after 4 weeks, after 8 weeks, or after 12 weeks. Using the methods provided herein can increase the AQLQ scores by at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, or at least 1.3.

[0055] In certain aspects, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, improves the AQLQ score no later than 4 weeks, no later than 8 weeks, no later than 9 weeks, no later than 10 weeks, no later than 12 weeks, no later than 16 weeks, no later than 20 weeks, no later than 24 weeks, no later than 28 weeks, no later than 32 weeks, no later than 36 weeks, no later than 40 weeks, no later than 44 weeks, no later than 48 weeks, or no later than 52 weeks.

[0056] In certain aspects, the use of the methods provided herein, i.e., administering benralizumab or an antigen-binding fragment thereof to a patient with asthma, improves an asthma questionnaire score (e.g., the Asthma Control Questionnaire (ACQ)), reduces the annualized attack frequency, and/or increases the forced expiratory volume in one second (FEV ₁ ).

[0057] In certain aspects, the patient is "eosinophil positive," meaning that the patient's asthma is likely eosinophilic in nature.

[0058] In certain aspects, the number of eosinophils in the blood of a patient with asthma has a specific value, for example, before the administration of benralizumab or an antigen-binding fragment thereof. The number of eosinophils in the blood can be measured, for example, using a complete blood count (CBC) with a white blood cell differential.

[0059] In certain aspects, the eosinophil count in the blood of the patient with asthma prior to administration of benralizumab or an antigen-binding fragment thereof is at least 300 cells/μL. In certain aspects, the eosinophil count in the blood of the patient with asthma prior to administration of benralizumab or an antigen-binding fragment thereof is at least 350 cells/μL, at least 400 cells/μL, at least 450 cells/μL, or at least 500 cells/μL.

[0060] In certain aspects, the eosinophil count in the blood of the patient with asthma prior to administration of benralizumab or an antigen-binding fragment thereof is less than 300 cells/μL. In certain aspects, the eosinophil count in the blood of the patient with asthma prior to administration of benralizumab or an antigen-binding fragment thereof is at least 100 cells/μL, at least 150 cells/μL, at least 180 cells/μL, at least 200 cells/μL, or at least 250 cells/μL.

[0061] In certain aspects, the patient with asthma has been prescribed or has used a medium dose of inhaled corticosteroids (ICS) prior to administration of benralizumab or an antigen-binding fragment thereof. The medium dose of ICS may be a dose of at least 600 mcg to 1200 mcg of budesonide daily, or an equivalent dose of another ICS.

[0062] In certain aspects, the patient with asthma has been prescribed or has used a high dose of ICS prior to administration of benralizumab or an antigen-binding fragment thereof. The high dose of ICS may be a dose of at least 1200 mcg of budesonide daily, or an equivalent dose of another ICS. The high dose of ICS may also be a dose of greater than 1200 mcg to 2000 mcg of budesonide daily, or an equivalent dose of another ICS.

[0063] In certain aspects, the patient with asthma has been prescribed or has used oral corticosteroids prior to administration of benralizumab or an antigen-binding fragment thereof. In certain aspects, administration of benralizumab or an antigen-binding fragment thereof reduces the use of oral corticosteroids in the patient with asthma. In certain aspects, administration reduces the use of oral corticosteroids in the patient with asthma by at least 50%.

[0064] In certain aspects, a patient with asthma was prescribed or used a long-acting beta agonist (LABA) prior to administration of benralizumab or an antigen-binding fragment thereof.

[0065] In certain aspects, a patient with asthma was prescribed or used both an ICS and a LABA prior to administration of benralizumab or an antigen-binding fragment thereof.

[0066] In certain aspects, the asthma patient has a blood eosinophil count of at least 300 cells/μL and has received a high dose of ICS prior to administration of benralizumab or an antigen-binding fragment thereof.

[0067] In certain aspects, the ACQ or ACQ-6 score of the asthma patient prior to administration of benralizumab or an antigen-binding fragment thereof is at least 1.5, at least 2.0, at least 2.5, at least 3.0, or at least 3.5. In certain aspects, the ACQ or ACQ-6 score of the asthma patient prior to administration of benralizumab or an antigen-binding fragment thereof is no more than 3.2, no more than 3.0, no more than 2.9, or no more than 2.8.

Examples

EXAMPLE 1: Patients and Methods

(a) SUBJECTS

[0068] Subjects in this study were required to be 18-75 years of age and weigh greater than 45 kg and less than or equal to 150 kg (greater than 100 lbs but less than or equal to 330 lbs). They also had to have a physician diagnosis of asthma for at least 12 months prior to screening and be prescribed daily use of either a moderate- or high-dose inhaled corticosteroid (ICS) and a concomitant long-acting beta-agonist (LABA), or any combination of sequential dosing of either a moderate-dose or high-dose ICS/LABA for at least 12 months prior to screening. The moderate- and high-dose ICS as defined in this study are shown in Table 1 below.

Table 1

Suggested comparative daily dosages for inhaled corticosteroids

Medicine Average daily dose (adults) High Daily Dose (Adults) Beclomethasone HFA/MDI
40 or 80 mcg/injection >240-480 mcg >480 mcg Budenosid DPI
90, 180 or 200 mcg/inhalation >600-1200 mcg >1200 mcg Ciclesonide HFA/MDI
80 or 160 mcg/inhalation >160-320 mcg >320-1280 mcg Flunisolide CFC/MDI
250 mcg/injection >1000-2000 mcg >2000 mcg Flunisolide HFA/MDI
80 mcg/injection >320-640 mcg >640 mcg Fluticasone
HFA/MDI: 44, 110 or 220 mcg/injection
DPI: 50, 100 or 250 mcg/injection >264-440 mcg
>300-500 mcg >440 mcg
>500 mcg Mometasone DPI
200 mcg/inhalation 400 mcg >400 mcg Triamcinolone acetonide CFC/MDI
75 mcg/injection >750-1500 mcg >1500 mcg

CFC=chlorofluorocarbon; DPI=dry powder inhaler; HFA=hydrofluoroalkane; MDI=metered dose inhaler

[0069] Subjects must have had a stable dose of other asthma controller medications for at least 30 days prior to Screening. Subjects must also have had at least 2, but no more than 6, documented asthma attacks in the 12 months prior to Screening that required the use of pulse systemic corticosteroid therapy. In addition, subjects' morning forced expiratory volume in 1 second (FEV ₁ ) before bronchodilator administration must have been at least 40% and less than 90% of predicted during the Screening/Run-In Period (described below). Subjects must also have met one of the following criteria:

a) Evidence of reversibility of airflow obstruction after bronchodilator use by ≥12% and ≥200 mL, documented no later than 36 months before randomization, or evidence of a positive response [PC20 ≤8 mg/mL] to methacholine challenge, documented no later than 36 months before randomization; OR

b) An increase in _FEV1 after bronchodilator use of ≥12% and ≥200 mL at the screening visit at week -3; OR

c) If a) and b) were not met and all other inclusion/exclusion criteria were met, subjects with an _FEV1 of ≥1.5 L and ≥60% of predicted at the week -2 screening visit could undergo methacholine challenge at the week -2 screening visit at centers where methacholine testing was available. If the subject achieved a positive response (PC20 ≤8 mg/mL), then this inclusion criterion was met.

[0070] In addition, the subject's Asthma Control Questionnaire (ACQ) score must have been at least 1.5 at least twice during the screening/run-in period.

[0071] Subjects were ineligible to participate if they had a smoking history of 10 pack-years or more, or had smoked within 12 months prior to screening, or had any condition (e.g., any low-eosinophil respiratory disease other than asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis) that, in the opinion of the investigator or medical monitor, would interfere with assessment. Subjects were also ineligible to participate if they had received oral corticosteroid pulse therapy or rapid-acting systemic corticosteroids within 30 days prior to screening or during the screening/run-in period.

(b) STUDY DESIGN

[0072] The study was a randomized, double-blind, placebo-controlled, dose-ranging, multicenter, phase 2b study (ClinicalTrials.gov number: NCT01238861) in which multiple doses of subcutaneous benralizumab were administered to patients with asthma. Benralizumab was administered at doses of 2, 20, or 100 mg, and patients were followed for 1 year. The study flow chart is shown in Fig. 1.

[0073] A 3-week screening/run-in period preceded administration of benralizumab or placebo. During the 3-week period, subjects continued to receive either the same ICS/LABA combination product at the medium or high dose as before study entry (ICS/LABA doses were required to be stable for 30 days prior to the 3-week screening/run-in period). Subjects continued to receive the same ICS/LABA dose throughout the study.

[0074] The benralizumab administration formulation contained benralizumab (50 mg/mL), 10 mM histidine, 10 mM histidine HCl monohydrate, 9% (w/v) trehalose dihydrate, and 0.004% (w/v) polysorbate 20, pH 6. The placebo administration formulation contained 10 mM histidine, 10 mM histidine hydrochloride monohydrate, 9% (w/v) trehalose dihydrate, and 0.02% (w/v) polysorbate 20, pH 6.

[0075] Subjects received two 1 mL subcutaneous (SC) injections of benralizumab or placebo four weeks apart for the first 3 doses at weeks 1 (day 1), 4, and 8, and then eight weeks later for the final 4 doses at weeks 16, 24, 32, and 40. After week 40, subjects were followed for an additional 12 weeks (through week 52). The day of the first dose of benralizumab or placebo was considered day 1.

[0076] The ACQ-6 was completed at each screening visit and weekly at home through the week 52 visit. Centers checked for subject compliance with the ACQ-6 at each visit through week 52. Specifically, the ACQ-6 was administered at Screening Visit 1 (i.e., Visit 1 on day -21) and then completed daily at home. The ACQ-6 was checked at Screening Visit 2 (i.e., Visit 2 on approximately day -14) if Visit 2 occurred, and at Screening Visit 3 (i.e., Visit 3 on approximately day -7). Compliance with the ACQ-6 at home was checked at Week 1 (day 1), Week 4, Week 8, Week 12, Week 16, Week 24, Week 40, and Week 52. Subjects were asked to recall how their asthma had been during the previous week by answering one question about bronchodilator use and 5 questions about symptoms.

[0077] Change from baseline (last valid assessment before the first study drug administration on Day 1) in mean ACQ-6 score was pooled by treatment and visit. Change from baseline in mean ACQ-6 score across visits could be analyzed using ANCOVA with treatment and baseline scores as possible covariates.

[0078] Subjects also completed asthma symptom diaries each morning at home. These diaries were reviewed at each screening visit (except the first screening visit) and daily through Week 52. In these diaries, subjects were asked to recall events that occurred to them related to the frequency and severity of daytime and nighttime symptoms, activity avoidance and limitation, asthma-related anxiety and fatigue, and rescue medication use. Each symptom of daytime frequency, daytime severity, and nighttime severity was rated by the subject from 0 (no symptoms) to 4 (most frequent/severe symptoms). A total symptom score was calculated as the average of the 3 symptom questions.

[0079] Subjects also completed the Asthma Quality of Life Questionnaire (Standard Version). The AQLQ[S] is a 32-item questionnaire that measures health-related quality of life experienced by patients with asthma. Juniper et al. Chest. 115: 1265–70 (1999). The AQLQ[S] was completed at the week 3 screening visit and day 1, and then 4 weeks later at home until the week 52 visit. Compliance was checked at some visits until the week 52 visit. The questionnaire contains 4 separate groups of questions (symptoms, types of activity limitations, emotional state, and environmental effects). Subjects were asked to recall their condition over the previous 2 weeks and score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score was calculated as the mean of responses to all questions. The 4 individual question group scores (symptoms, types of activity limitations, emotional state, and environmental effects) represent the mean of responses to questions in each question group. An individual improvement in both the total score and the individual question group scores of 0.5 was considered the minimal important change, with score changes of >1.5 considered the major important change. Juniper et al. J Clin Epidemiol. 47: 81–7 (1994).

(c) SAFETY ASSESSMENTS

[0080] Adverse events were monitored after administration of placebo or benralizumab. Other assessments included physical examination, vital sign monitoring, and laboratory measurements.

EXAMPLE 2: Results

(a) STUDY INCLUSION AND BASELINE CHARACTERISTICS

[0081] Baseline characteristics of all randomized subjects who received any dose of study drug are presented in Table 2 below. The median ICS dose for the patient populations was 1100 budesonide equivalents overall, 700 budesonide equivalents in the medium-dose group, and 1600 budesonide equivalents in the high-dose group.

Table 2

Demographic data regarding baseline eosinophil (EOS) level

POPULATION PLACEBO
EOS <300 BENRALIZUMAB
EOS < 300 PLACEBO
EOS >=300 BENRALIZUMAB
EOS >=300 N 139 151 83 232 Average age (years) 50.3 51.2 45.2 46.3 Female gender (%) 71 70 66 68 White race (%) 76 80 64 65 BMI (average) 29.6 29.2 28.8 28.5 Average EOS cells/µl 149 156 542 548-615 Systematic intake of OCS (%) 2.2% 7.9% 4.8% 4.3% Predicted FEV ₁ (L) % 70.0 54-69 65 64-67 Reversibility (%) 12.5 13-18 15.5 17-19 History of seizures 2,2 2.3-2.5 2,2 2.3-2.5 ACQ Baseline 2.5 2.5-2.8 2.6 2.4-2.7 Childhood asthma YES 32% 33-38% 40% 37-41% History of nasal polyps YES 10.8% 11.9% 14.5% 19.3% Average value of FE _NO , ppb 22.1 21-39 34.8 34-42

OCS=oral corticosteroids; FEV1=forced expiratory volume in 1 second; ACQ=asthma control questionnaire and FENO=proportion of exhaled nitric oxide

[0082] Baseline characteristics of randomized subjects who received any dose of study drug and had a baseline eosinophil count of at least 300 cells/μL are shown in Table 3 below.

Table 3

Demographic data regarding ICS with baseline EOS count of at least 300 cells/µL

POPULATION PLACEBO
AVERAGE DOSE OF ICS BENRALIZUMAB
AVERAGE DOSE OF ICS PLACEBO
HIGH DOSE ICS BENRALIZUMAB
HIGH DOSE ICS N 43 121 40 111 Average age (years) 45 46-47 45 45-47 Female gender (%) 65 63 68 70-79 White race (%) 56 66 73 63 BMI (average) 27.3 27.6-28.3 30.3 27.8-30.0 Average EOS cells/µl 480 462-625 608 605-656 Systematic intake of OCS (%) 0 0 10% 9% Predicted FEV ₁ (L) % 68.8 64-70 60 63-65 Reversibility (%) 16% 17-23% 15% 14-21% History of seizures 2,2 2.1-2.5 2,3 2.4-2.5 ACQ Baseline 2.6 2.3-2.6 2.7 2.6-2.8 Childhood asthma YES 42% 36% 38% 27-53% History of nasal polyps YES 14% 11% 15% 23-37% Average value of FE _NO , ppb 38.3 35-45 31.0 33-39

OCS=oral corticosteroids; FEV1=forced expiratory volume in 1 second; ACQ=asthma control questionnaire and FENO=proportion of exhaled nitric oxide

(b) EFFICIENCY

[0083] The effects of benralizumab administration on ACQ-6 are shown in Figs. 2-8. For example, the data in Fig. 2 demonstrate that by week 24, patients with blood eosinophil counts of at least 300 cells/μL who received 2, 20, or 100 mg of benralizumab showed a decrease in ACQ-6 scores. Similar results were also observed at week 52 (Fig. 3). The data in Fig. 4 demonstrate that ACQ-6 scores improved in patients receiving either medium-dose or high-dose ICS, but the improvement was greater in patients receiving high-dose ICS. The data in Fig. 5 compares the changes in ACQ-6 scores in patients with blood eosinophil counts less than 300 cells/μL who received mid-dose ICS with the changes in patients who received high-dose ICS, and the data in Fig. 6 compares the changes in ACQ-6 scores in patients with blood eosinophil counts of at least 300 cells/μL who received mid-dose ICS with the changes in patients who received high-dose ICS. A more detailed distribution by eosinophil count is shown in Fig. 7. As shown in Fig. 8, the difference in ACQ-6 scores between patients receiving benralizumab and placebo could be observed as early as week 7 in patients with blood eosinophil counts of at least 300 cells/μL.

[0084] The effects of benralizumab administration on total symptom scores in asthma symptom diaries are shown in Figure 9. Patients with blood eosinophil counts of at least 300 cells/μL who received 100 mg benralizumab showed reductions in total symptom scores according to the diary of greater than 0.5.

[0085] The effects of benralizumab administration on AQLQ scores are shown in Fig. 10. Patients with blood eosinophil counts of at least 300 cells/μL who received benralizumab showed increases in AQLQ scores of greater than 0.5 or 1.0.

(c) SECURITY

[0086] Treatment-emergent adverse events (TEAEs) occurred in patients treated with benralizumab at a rate approximately 10 percent higher than in patients treated with placebo. Treatment-emergent serious adverse events (TE-SAEs) occurred at a similar rate in patients treated with benralizumab and placebo. TEAEs and TE-SAEs did not show dose-response in patients treated with benralizumab.

(d) DRUG ANTIBODIES

[0087] Development of anti-drug antibodies (ADAs), benralizumab, was inversely related to dose, with the highest proportion of ADA-positive subjects observed at the 2 mg dose (see Table 4 below). The incidence of high ADA titers (≥400) was 12% and 9% in the 20 and 100 mg dose groups, respectively. High ADA titers were associated with reduced benralizumab concentrations and variable degrees of eosinophil recovery, when present. The pharmacokinetic/pharmacodynamic (PK/PD) impact of high ADA titers decreased with exposure to higher doses of drug. No patterns were observed between TEAEs and ADA.

Table 4

Antibodies to the drug in week 24

Treatment group Total number of subjects % of subjects with positive ADA titers % of subjects with ADA titers ≥400 Placebo 222 8.1% (n=18) 3% (n=6) Benralizumab 2 mg 81 34.6% (n=28) 23% (n=19) Benralizumab 20 mg 81 18.5% (n=15) 12% (n=10) Benralizumab 100 mg 222 21.2% (n=47) 9% (n=20)

[0088] Based on both PK and immunologic considerations, new patients will receive a dose of 30 mg benralizumab. In some patients, the 30 mg benralizumab dose will be administered every four weeks. In some patients, the 30 mg benralizumab dose will be administered once every four weeks for three doses, and then once every eight weeks thereafter.

(e) DISCUSSION

[0089] This study demonstrates that benralizumab normalizes asthma symptoms as measured by the ACQ-6. Normalization was observed at all doses, but a greater magnitude of benefit was evident at the 20 and 100 mg doses compared with the 2 mg dose. In addition, ACQ-6 scores improved to a greater extent with high-dose ICS/LABA than with mid-dose ICS/LABA. Asthma symptom diaries also reported improvements in overall symptom scores based on daytime symptom frequency, daytime symptom severity, and night-time symptom severity. Increased AQLQ scores in patients also indicate symptom normalization.

EXAMPLE 3: Additional Dose Assessment

[0090] Dose-efficacy modeling was performed to identify additional doses of benralizumab that reduce annualized attack frequency and are safe and well tolerated. Modeling showed that a dose of approximately 30 mg was the minimum effective dose, producing 90% of the maximal treatment effect. Therefore, patients with uncontrolled asthma received subcutaneous injections of 30 mg benralizumab or placebo. Doses of 30 mg were administered (i) every four weeks or (ii) every four weeks for eight weeks (3 doses) and then eight weeks later (i.e., 8 weeks, including an additional dose at week 4). The number of attacks in patients receiving 30 mg benralizumab was compared with the number of attacks in patients receiving placebo to demonstrate that doses of 30 mg benralizumab reduced annualized attack frequency. Additionally, the number of attacks was analyzed in patients with baseline blood eosinophil counts of at least 300 cells/μL to demonstrate that doses of 30 mg benralizumab may be effective in reducing annual attack frequency in these patients.

[0091] Those skilled in the art will recognize, or be able to discover with no more than routine experimentation, many equivalents to the specific aspects of the present disclosure described herein. Such equivalents are intended to be covered by the following claims.

[0092] This document cites various publications, the disclosures of which are incorporated by reference in their entireties.

[0093] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be apparent that certain changes and modifications can be made within the scope of the appended claims.

SEQUENCE LIST

SEQ ID NO:1

>US20100291073_1 Sequence 1 from US Patent Document 20100291073 Organism: Homo sapiens

DIQMTQSPSSLSSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQGYTLPYTFGQGTKVEIK

SEQ ID NO:2

>US20100291073_2 Sequence 2 of US Patent Document 20100291073 Organism: Homo sapiens

DIQMTQSPSSLSSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQGYTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ

ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO:3

>US20100291073_3 Sequence 3 from US Patent Document 20100291073 Organism: Homo sapiens

EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHWVRQRPGQGLAWMGYINPYNDGTKYNERFKGKVTITSDRSTSTVY

MELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVTVSS

SEQ ID NO:4

>US20100291073_4 Sequence 4 from US Patent Document 20100291073 Organism: Homo sapiens

EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHWVRQRPGQGLAWMGYINPYNDGTKYNERFKGKVTITSDRSTSTVY

MELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV

SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG

KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP

VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO:5

>US20100291073_5 Sequence 5 from US Patent Document 20100291073 Organism: Homo sapiens

DLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETRITESKCVTILHKGFSASVRT

ILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTEDNYSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTE

ECQEYSKDTLGRNIACWFPRTFILSKGRDWLAVLVNGSSKHSAIRPFDQLFALHAIDQINPPLNVTAEIEGTRLSIQWEK

PVSAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAGLWSEWSQPIYVGNDEHKPLR

EWFVIVIMATICFILLILSLICKICHLWIKLFPPIPAPKSNIKDLFVTTNYEKAGSSETEIEVICYIEKPGVETLEDSVF

SEQ ID NO:6

>US20100291073_6 Sequence 6 from US Patent Document 20100291073 Organism: Mus musculus

DLLNHKKFLLLPPVNFTIKATGLAQVLLHWDPNPDQEQRHVDLEYHVKINAPQEDEYDTRKTESKCVTPLHEGFAASVRT

ILKSSHTTLASSWVSAELKAPPGSPGTSVTNLTCTTHTVVSSHTHLRPYQVSLRCTWLVGKDAPEDTQYFLYYRFGVLTE

KCQEYSRDALNRNTACWFPRTFINSKGFEQLAVHINGSSKRAAIKPFDQLFSPLAIDQVNPPRNVTVEIESNSLYIQWEK

PLSAFPDHCFNYELKIYNTKNGHIQKEKLIANKFISKIDDVSTYSIQVRAAVSSPCRMPGRWGEWSQPIYVGKERKSLVE

WHLIVLPTAACFVLLIFSLICRVCHLWTRLFPPVPAPKSNIKDLPVVTEYEKPSNETKIEVVHCVEEVGFEVMGNSTF

SEQ ID NO:7 - VH CDR1

SYVIH

SEQ ID NO:8 - VH CDR2

YINPYNDGTKYNERFKG

SEQ ID NO:9 - VH CDR3

EGIRYYGLLGDY

SEQ ID NO:10 - VL-CDR1

GTSEDIINYLN

SEQ ID NO:11 - VL CDR2

HTSRLQS

SEQ ID NO:12 - VL CDR3

QQGYTLPYT

SEQUENCE LIST

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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys

85 90 95

Gly Arg Glu Gly Ile Arg Tyr Tyr Gly Leu Leu Gly Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 5

<211> 400

<212> PROTEIN

<213> Homo sapiens

<400> 5

Asp Leu Leu Pro Asp Glu Lys Ile Ser Leu Leu Pro Pro Val Asn Phe

1 5 10 15

Thr Ile Lys Val Thr Gly Leu Ala Gln Val Leu Leu Gln Trp Lys Pro

20 25 30

Asn Pro Asp Gln Glu Gln Arg Asn Val Asn Leu Glu Tyr Gln Val Lys

35 40 45

Ile Asn Ala Pro Lys Glu Asp Asp Tyr Glu Thr Arg Ile Thr Glu Ser

50 55 60

Lys Cys Val Thr Ile Leu His Lys Gly Phe Ser Ala Ser Val Arg Thr

65 70 75 80

Ile Leu Gln Asn Asp His Ser Leu Leu Ala Ser Ser Trp Ala Ser Ala

85 90 95

Glu Leu His Ala Pro Pro Gly Ser Pro Gly Thr Ser Ile Val Asn Leu

100 105 110

Thr Cys Thr Thr Asn Thr Thr Glu Asp Asn Tyr Ser Arg Leu Arg Ser

115 120 125

Tyr Gln Val Ser Leu His Cys Thr Trp Leu Val Gly Thr Asp Ala Pro

130 135 140

Glu Asp Thr Gln Tyr Phe Leu Tyr Tyr Arg Tyr Gly Ser Trp Thr Glu

145 150 155 160

Glu Cys Gln Glu Tyr Ser Lys Asp Thr Leu Gly Arg Asn Ile Ala Cys

165 170 175

Trp Phe Pro Arg Thr Phe Ile Leu Ser Lys Gly Arg Asp Trp Leu Ala

180 185 190

Val Leu Val Asn Gly Ser Ser Lys His Ser Ala Ile Arg Pro Phe Asp

195 200 205

Gln Leu Phe Ala Leu His Ala Ile Asp Gln Ile Asn Pro Pro Leu Asn

210 215 220

Val Thr Ala Glu Ile Glu Gly Thr Arg Leu Ser Ile Gln Trp Glu Lys

225 230 235 240

Pro Val Ser Ala Phe Pro Ile His Cys Phe Asp Tyr Glu Val Lys Ile

245 250 255

His Asn Thr Arg Asn Gly Tyr Leu Gln Ile Glu Lys Leu Met Thr Asn

260 265 270

Ala Phe Ile Ser Ile Ile Asp Asp Leu Ser Lys Tyr Asp Val Gln Val

275 280 285

Arg Ala Ala Val Ser Ser Met Cys Arg Glu Ala Gly Leu Trp Ser Glu

290 295 300

Trp Ser Gln Pro Ile Tyr Val Gly Asn Asp Glu His Lys Pro Leu Arg

305 310 315 320

Glu Trp Phe Val Ile Val Ile Met Ala Thr Ile Cys Phe Ile Leu Leu

325 330 335

Ile Leu Ser Leu Ile Cys Lys Ile Cys His Leu Trp Ile Lys Leu Phe

340 345 350

Pro Pro Ile Pro Ala Pro Lys Ser Asn Ile Lys Asp Leu Phe Val Thr

355 360 365

Thr Asn Tyr Glu Lys Ala Gly Ser Ser Glu Thr Glu Ile Glu Val Ile

370 375 380

Cys Tyr Ile Glu Lys Pro Gly Val Glu Thr Leu Glu Asp Ser Val Phe

385 390 395 400

<210> 6

<211> 398

<212> PROTEIN

<213> Mus musculus

<400> 6

Asp Leu Leu Asn His Lys Lys Phe Leu Leu Leu Pro Pro Val Asn Phe

1 5 10 15

Thr Ile Lys Ala Thr Gly Leu Ala Gln Val Leu Leu His Trp Asp Pro

20 25 30

Asn Pro Asp Gln Glu Gln Arg His Val Asp Leu Glu Tyr His Val Lys

35 40 45

Ile Asn Ala Pro Gln Glu Asp Glu Tyr Asp Thr Arg Lys Thr Glu Ser

50 55 60

Lys Cys Val Thr Pro Leu His Glu Gly Phe Ala Ala Ser Val Arg Thr

65 70 75 80

Ile Leu Lys Ser Ser His Thr Thr Leu Ala Ser Ser Trp Val Ser Ala

85 90 95

Glu Leu Lys Ala Pro Pro Gly Ser Pro Gly Thr Ser Val Thr Asn Leu

100 105 110

Thr Cys Thr Thr His Thr Val Val Ser Ser His Thr His Leu Arg Pro

115 120 125

Tyr Gln Val Ser Leu Arg Cys Thr Trp Leu Val Gly Lys Asp Ala Pro

130 135 140

Glu Asp Thr Gln Tyr Phe Leu Tyr Tyr Arg Phe Gly Val Leu Thr Glu

145 150 155 160

Lys Cys Gln Glu Tyr Ser Arg Asp Ala Leu Asn Arg Asn Thr Ala Cys

165 170 175

Trp Phe Pro Arg Thr Phe Ile Asn Ser Lys Gly Phe Glu Gln Leu Ala

180 185 190

Val His Ile Asn Gly Ser Ser Lys Arg Ala Ala Ile Lys Pro Phe Asp

195 200 205

Gln Leu Phe Ser Pro Leu Ala Ile Asp Gln Val Asn Pro Pro Arg Asn

210 215 220

Val Thr Val Glu Ile Glu Ser Asn Ser Leu Tyr Ile Gln Trp Glu Lys

225 230 235 240

Pro Leu Ser Ala Phe Pro Asp His Cys Phe Asn Tyr Glu Leu Lys Ile

245 250 255

Tyr Asn Thr Lys Asn Gly His Ile Gln Lys Glu Lys Leu Ile Ala Asn

260 265 270

Lys Phe Ile Ser Lys Ile Asp Asp Val Ser Thr Tyr Ser Ile Gln Val

275 280 285

Arg Ala Ala Val Ser Ser Pro Cys Arg Met Pro Gly Arg Trp Gly Glu

290 295 300

Trp Ser Gln Pro Ile Tyr Val Gly Lys Glu Arg Lys Ser Leu Val Glu

305 310 315 320

Trp His Leu Ile Val Leu Pro Thr Ala Ala Cys Phe Val Leu Leu Ile

325 330 335

Phe Ser Leu Ile Cys Arg Val Cys His Leu Trp Thr Arg Leu Phe Pro

340 345 350

Pro Val Pro Ala Pro Lys Ser Asn Ile Lys Asp Leu Pro Val Val Thr

355 360 365

Glu Tyr Glu Lys Pro Ser Asn Glu Thr Lys Ile Glu Val Val His Cys

370 375 380

Val Glu Glu Val Gly Phe Glu Val Met Gly Asn Ser Thr Phe

385 390 395

<210> 7

<211> 5

<212> PROTEIN

<213> Homo sapiens

<400> 7

Ser Tyr Val Ile His

1 5

<210> 8

<211> 17

<212> PROTEIN

<213> Homo sapiens

<400> 8

Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Lys

1 5 10 15

Gly

<210> 9

<211> 12

<212> PROTEIN

<213> Homo sapiens

<400> 9

Glu Gly Ile Arg Tyr Tyr Gly Leu Leu Gly Asp Tyr

1 5 10

<210> 10

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 10

Gly Thr Ser Glu Asp Ile Ile Asn Tyr Leu Asn

1 5 10

<210> 11

<211> 7

<212> PROTEIN

<213> Homo sapiens

<400> 11

His Thr Ser Arg Leu Gln Ser

1 5

<210> 12

<211> 9

<212> PROTEIN

<213> Homo sapiens

<400> 12

Gln Gln Gly Tyr Thr Leu Pro Tyr Thr

1 5

<---

Claims (11)

1. A method of treating asthma, comprising administering to a patient from about 2 mg to about 100 mg of benralizumab or an antigen-binding fragment thereof, wherein the effectiveness of treating asthma is determined by improving the score according to an asthma questionnaire in a patient with asthma, wherein the asthma questionnaire is selected from the group consisting of the Asthma Control Questionnaire (ACQ), the Asthma Control Questionnaire-6 (ACQ-6) and the Asthma Quality of Life Questionnaire (AQLQ). 2. The method of claim 1, wherein the questionnaire assesses at least one symptom selected from the group consisting of night awakening, symptoms on awakening, activity limitation, shortness of breath, wheezing, use of a rescue medication, daytime symptom frequency and severity, nighttime symptom frequency and severity, activity avoidance and limitation, asthma-related anxiety and fatigue. 3. The method of claim 2, wherein the questionnaire assesses nocturnal awakening, symptoms upon awakening, activity limitation, shortness of breath, wheezing, and use of an emergency medication. 4. The method according to claim 2, wherein the questionnaire assesses the frequency of symptoms during the daytime, the severity of symptoms during the daytime, and the severity at night. 5. The method of claim 1, wherein benralizumab or an antigen-binding fragment thereof is administered at a rate of approximately 20 mg per dose. 6. The method of claim 1, wherein benralizumab or an antigen-binding fragment thereof is administered at a rate of approximately 30 mg per dose. 7. The method of claim 1, wherein benralizumab or an antigen-binding fragment thereof is administered at a rate of approximately 100 mg per dose. 8. The method according to any one of claims 1 to 7, wherein benralizumab or an antigen-binding fragment thereof is administered from once every four weeks to once every twelve weeks. 9. The method according to claim 8, wherein benralizumab or an antigen-binding fragment thereof is administered once every four weeks. 10. The method according to claim 8, wherein benralizumab or an antigen-binding fragment thereof is administered once every eight weeks. 11. The method according to claim 8, wherein benralizumab or an antigen-binding fragment thereof is administered once every four weeks for twelve weeks, and then once every eight weeks.