NZ730541B2 - Use of reslizumab to treat moderate to severe eosinophilic asthma - Google Patents

Abstract

Disclosed herein are methods of treating moderate to severe eosinophilic asthma in a patient comprising: 1) identifying a patient having moderate to severe eosinophilic asthma, wherein the patient's symptoms are inadequately controlled with a current asthma therapeutic and wherein the patient's blood eosinophil levels are equal to or greater than 400/µL.; and 2) administering to said patient a therapeutically effective dose of reslizumab.

Description

USE OF RESLIZUMAB TO TREAT MODERATE TO SEVERE EOSINOPHILIC ASTHMA CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US. Provisional Application No. 62/047,248, ?led September 8, 2014, US. Provisional Application No. 62/091,150, ?led December 12, 2014, US. ional Application No. 62/168,007, ?led May 29, 2015, and US. ional Application No. 62/191,690, ?led July 13, 2015. The contents of each of these applications are hereby incorporated by nce in their entirety.

TECHNICAL FIELD Disclosed herein are methods of treating moderate to severe eosinophilic asthma. More speci?cally, provided herein are methods of treating patients that are inadequately controlled with a current asthma therapeutic and who have a blood eosinophil level equal to or greater than 400/uL by administering to said patient a therapeutically effective dose of reslizumab.

BACKGROUND Asthma is a common, chronic atory condition that affects approximately 12% of adults and 10% of children and adolescents; it is estimated that 300 million people worldwide suffer from this condition. Each day in the United States, approximately 44,000 individuals have asthma attacks, resulting in missed school/work, emergency room visits or admission to a hospital, and even death. Asthma is characterized by in?ammation, and narrowing, of the air passages leading to wheezing, chest ess, shortness of breath, and coughing.

Common medications for the treatment of asthma include inhaled osteroids and/or long acting Bz—agonists. These medications, r, may inadequately control the t’s asthma symptoms. Patients with inadequately lled severe persistent asthma are at risk of exacerbations, hospitalization and death, and often have impaired quality of life. Thus, new therapeutics are needed to treat patients whose asthma is inadequately controlled. The enclosed methods address these and other important needs.

Disclosed herein are s of treating moderate to severe eosinophilic asthma in a patient comprising: 1) identifying a patient having moderate to severe eosinophilic asthma, _ 1 _ wherein the patient’s symptoms are inadequately controlled with a current asthma therapeutic and wherein the patient’s blood phil levels are equal to or greater than 400/uL; and 2) administering to said patient a therapeutically effective dose of umab.

BRIEF PTION OF THE DRAWINGS The summary, as well as the following detailed description, is r understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings exemplary embodiments of the invention; however, the invention is not limited to the speci?c s disclosed. In the drawings: comprising FIGS. 1A — 1B, represent the change (SE) from baseline in FEV1 by treatment group and visit (Fig. 1A) and overall change from baseline (primary efficacy) in FEV1 (Fig. 1B) after 16 weeks of treatment in study 1. All inferential statistics are derived from MMRM with ent, visit, ent by visit interaction, age group, history of asthma exacerbation in the previous 12 months, height, baseline, sex, and patient as a random effect.

Data are least-squared means 1 standard error. A=treatment difference (reslizumab — placebo).

SE: rd error; LS=Least Squares. * p50.05, ** p:0.005 versus placebo. P values are not adjusted to control for multiplicity. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; reslizumab 3.0 mg/kg = longer hashes. comprising FIGS. 2A—2B, represents the change (SE) from baseline to each visit in FVC by treatment group (Fig. 2A) and overall change from baseline in FVC (Fig. 2B) after 16 weeks of treatment in study 1. SE: standard error; LS=Least Squares. * p50.05 versus placebo. P values are not adjusted to control for multiplicity. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; umab 3.0 mg/kg = longer hashes. sing FIGS. 3A—3B, represent the change (SE) from baseline to each visit in FEF25%_75% by visit and treatment group (Fig 3A) and the l change from baseline in 75% () after 16 weeks of treatment in study 1. All inferential statistics are derived from MMRM with treatment, visit, treatment by visit interaction, age group, history of asthma exacerbation in the previous 12 months, height, baseline, sex, and patient as a random effect. Data are least-squared means i standard error. A=treatment difference (reslizumab — placebo). Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; reslizumab 3.0 mg/kg = longer hashes. represents the change from baseline in FEV1 over 16 weeks by treatment group (subpopulation analysis set — patients with a ne FEV1 % predicted of 585%) — in _ 2 _ study 1. LS=Least Squares; ndard error. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; reslizumab 3 .0 mg/kg = longer hashes. comprising FIGS. 5A—5B, ents change (SE) from baseline to each visit in asthma control questionnaire (ACQ) score by treatment group () and the overall change from baseline in ACQ scores () after 16 weeks of treatment in study 1. All inferential statistics are derived from MMRM with ent, visit, treatment by visit interaction, age group, history of asthma exacerbation in the previous 12 months, , baseline, sex, and patient as a random . Data are least-squared means i standard error. Negative changes in ACQ indicate improved asthma control. The minimal clinically important difference for ACQ is 0.5 units. A=treatment difference zumab — placebo). * p50.05, ** 5 versus placebo.

P values are not adjusted to control for multiplicity. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; umab 3.0 mg/kg = longer hashes. represents the proportion of subjects completing study 1 and achieving minimal clinically important differences (0.5 Units) in ACQ score from baseline. * p S 0.05; # p = . P value for comparison of active and placebo groups is obtained from the CMH test strati?ed by age group and history of asthma exacerbation in the previous 12 months. Placebo = left bar in each group; reslizumab 0.3 mg/kg = middle bar in each group; reslizumab 3.0 mg/kg = right bar in each group. comprising FIGS. 7A—7B, represent the change from baseline to week 16 in asthma quality of life questionnaire (AQLQ) score () and the proportion of patients achieving at least 0.5 improvement from baseline to week 16 in AQLQ () by treatment group in study 1. AQLQ was only assessed at baseline and at week 16. The minimally clinical important difference for AQLQ is 0.5 units. Data are least-squared means in standard error. comprising FIGS. 8A — 8B, represent the change (SE) from baseline to each visit in asthma symptom utility index (AUSI) score () and the overall change from baseline over 16 weeks of treatment in ASUI () by ent group in study 1. SE: standard error; LS=Least Squares. * pS0.05, ** 5 versus placebo. P values are not adjusted to control for licity. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; reslizumab 3.0 mg/kg = longer . comprising FIGS. 9A-9B, represent the change (SE) from baseline to each Visit in short acting beta agonist (SABA) use by visit and treatment group () and the change from baseline in average daily use of SABA by treatment group (FIG 9B) in study 1.

SE: standard error; LS=Least Squares. * p:0.05, ** p:0.005. P values are not adjusted to control for licity. Placebo = solid line; reslizumab 0.3 mg/kg = shorter hashes; reslizumab 3.0 mg/kg = longer hashes. , comprising FIGS. 10A—10B, represent the blood eosinophil counts over time by treatment group in study 1. The blood eosinophil counts were measured using a standard CBC with differential blood test at each scheduled visit. 10A) Placebo = left data set in each group; reslizumab 0.3 mg/kg = middle data set in each group; reslizumab 3.0 mg/kg = right data set in each group. 10B) Placebo = solid line; umab 0.3 mg/kg = shorter hashes; reslizumab 3.0 mg/kg = longer hashes. , comprising FIGS. llA-l 1B, represent the mean change from baseline (+/- SD) in serum ECP at Week 8 and 16 (A) and Serum EDN at Week 8 and 16 (B) in study 1. Placebo = solid line; reslizumab 0.3 mg/kg = r hashes; umab 3.0 mg/kg = longer hashes. , comprising FIGS. l2A—12C, represented the time to First Clinical Asthma Exacerbation in (A) Study 2 and (B) Study 3 plus pooled analyses (studies 2 and 3) of CAE rate ratios (C). The panels A and B show the time to first CAE against the probability of not experiencing an exacerbation. Median (95% CI) times to first CAE are presented. Panel C presents the CAB rate—ratios for pooled populations Study 2 plus Study 3 according to major background therapy. *P S 0.05, **P S 0.01, ***P 5 0.001. CI, con?dence interval; NA, not available. In both A) and B) placebo = top line; reslizumab 3.0 mg/kg = bottom line. , sing FIGS. l3A—13D, represent changes in FEV1 and AQLQ over 52 weeks for Study 2 (A and C respectively) and Study 3 (B and D respectively). The secondary ef?cacy — FEV1 over time — from study 2 (A) and study 3 (B), comparing the LS mean change from baseline in FEVI at baseline and for each visit. Changes in key lung function ters throughout the 52—Week study. In both studies FEV1 improved by Week 4 and was maintained until study end. Quality of life was improved at the ?rst measured time point (Week 16) and was maintained until Week 52. In each A)—D), placebo = solid, bottom line; reslizumab = hashed, top line. , comprising FIGS. l4A-14B, represent the change from Baseline in Asthma Control Questionnaire Score over the 52-Week Treatment Period in (A) Study 2 and (B) Study 3 (Intention-to-Treat tion). The panels show the least-square mean (standard error) change from baseline in Asthma l Questionnaire score over the 52—week study period and at —treatment. *P S 0.05, **P S 0.01, ***P 5 0.001. In each A)-B), placebo = solid, top line; reslizumab = hashed, bottom line. , comprising FIGS. ISA—15B, represent the change from ne in Asthma m Utility Index Score over the 52—Week Treatment Period in (A) Study 2 and (B) Study 3 (Intention-to-Treat Population). The panels show the least-square mean (standard error) change from baseline in Asthma Symptom Utility Index score over the 52—week study period and at end—of—treatment. *P S 0.05, **P S 0.01, ***P S 0.001. In each A)—B), placebo = solid, bottom line; reslizumab = hashed, top line. , comprising FIGS. l6A—16B, represent scatter Plot of Blood phil Count over the 52-Week Treatment Period in (A) Study 2 and (B) Study 3 tion-to-Treat Population). The panels show individual blood eosinophil counts in both treatment arms over the 52-Week study period and treatment follow-up. Patients were required to have a blood eosinophil count of at least 400/uL at least once during the screening period prior to being randomized. As this value did not arily occur at baseline, the baseline eosinophil counts depicted for the randomized population in the ?gure include some patients with values below 400/"L. In each A)-B), placebo = left data points in each group; reslizumab = right data points in each group. represents a pooled sub—analyses of FEV1 least—squares means at over the first 16 weeks and from baseline to study end (week 52) for patient populations with different concomitant medication pro?les. , comprising FIGS. 18A—18G, represent the baseline blood eosinophil category (A), the change in FEV1 (week 16) vs. baseline eosinophils: linear regression model (B); the mean FEV1 over time by treatment: overall population (C) (error bars are rd error of mean); reslizumab treatment effect by baseline eosinophil count at week 16: FEV1 (D) (*P=0.0436; Error bars are standard error of the difference between reslizumab and placebo; Treatment ence, corresponding SE, and P value are from MMRM); the reslizumab treatment effect by ne eosinophil count at week 16: ACQ—7 (E) (Error bars are standard error of the difference between reslizumab and placebo; Treatment difference and ponding SE are from MMRM); the umab treatment effect by baseline eosinophil count at week 16: rescue medication (F) (Error bars are standard error of the difference between reslizumab and placebo; Treatment difference and corresponding SE are from MMRM); and the reslizumab treatment effect by baseline eosinophil count at week 16: PVC (G) (Error bars are standard error of the difference n reslizumab and placebo; Treatment difference and corresponding SE are from MMRM). In A) placebo = left bar in each group; reslizumab = right bar in each group. In B) placebo = les; reslizumab = circles. _ 5 _ , comprising FIGS. l9A—19B, represents (A) annual rate of asthma exacerbations (clinical asthma exacerbations : CAE) and (B) overall change in lung function (FEV1) in the overall patient population, patients not having late-onset asthma (less than 40 years old at time of sis "age < 40") and ts having late—onset asthma (greater than or equal to 40 years old at time of diagnosis "age 2 40"). , comprising FIGS. 20A—20B, represents the in?uence of ne eosinophil counts higher than a 400/ul cut—off, in pooled 52 week exacerbation studies, on (A) percent reduction in CAEs and (B) FEVl. In B), 16 weeks = left bar in each group; 52 weeks = right bar in each group. , comprising FIGS. 21A-21B, illustrates the in?uence of disease severity (based on background controller tion) on reslizumab y on (A) CAE (clinical asthma exacerbation) and (B) FEVl. Pooled results (across studies 2 and 3) for CAE rate ratios by level of asthma therapy at entry. The background medication requirement for reslizumab was at least medium dose ICS (Z 440 pg ?uticasone or equivalent) in another controller. The majority of patients were using a LABA. *reslizumab relative to placebo, CAE (clinical asthma exacerbations), OCS (oral corticosteroids), ICS (inhaled corticosteroids), LABA (long—acting beta agonist), LS (least squares).

In the above ?gures and the results that follow herein, all inferential statistics are derived from mixed model repeated measures (MMRM) with treatment, visit, ent by visit interaction, age group, history of asthma exacerbation in the previous 12 months, height, ne, sex, and patient as a random .

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The disclosed methods may be understood more y by reference to the following detailed description taken in connection with the accompanying ?gures, which form a part of this disclosure. It is to be understood that the disclosed s are not limited to the speci?c methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

Similarly, unless speci?cally otherwise stated, any description as to a possible mechanism or mode of action or reason for ement is meant to be illustrative only, and the disclosed methods are not to be constrained by the correctness or ectness of any such suggested mechanism or mode of action or reason for improvement.

When a range of values is expressed, another embodiment es from the one particular value and/or to the other particular value. Further, reference to values stated in ranges e each and every value within that range. All ranges are inclusive and combinable. When values are expressed as approximations, by use of the antecedent "about," it will be tood that the ular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly es otherwise It is to be iated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

As used , the ar forms ‘6 77 (C a an," and "the" include the plural.

The following abbreviations are used throughout the disclosure: ACQ a Control Questionnaire); AQLQ a Quality of Life Questionnaire); ASUI (Asthma Symptom Utility Index); CAE (clinical asthma exacerbation); FEV1 (forced expiratory volume in 1 second); FVC d vital capacity); Forced Expiratory Flow Rate (FEF25%_75%); ICS (inhaled corticosteroid); LABA acting beta—agonist); SABA (short-acting beta-agonist); AE (adverse event).

The term "about" when used in reference to numerical , cutoffs, or specific values is used to indicate that the d values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term "about" is used to encompass variations of i 10% or less, variations ofi 5% or less, variations of i 1% or less, variations of :: 0.5% or less, or variations of i 0.1% or less from the ied value.

As used herein, "treating" and like terms refer to a reducing the severity and/or frequency of asthma symptoms, eliminating asthma symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of asthma symptoms and/or their underlying cause, and improving or remediating damage caused, directly or indirectly, by asthma.

As used herein, "administering to said patient" and similar terms indicate a procedure by which reslizumab is injected into a patient such that target cells, tissues, or segments of the body of the subject are contacted with reslizumab. _ 7 _ As used herein, "injected" es intravenous (iv) or subcutaneous (sub—Q) administration. In some embodiments, for example, reslizumab can be administered to said patient intravenously. In other embodiments, reslizumab can be administered to said patient subcutaneously.

As used herein, the phrase "therapeutically effective dose" refers to an amount of a reslizumab, as described herein, effective to e a ular biological or therapeutic result such as, but not limited to, biological or eutic results disclosed, bed, or exempli?ed herein. The therapeutically ive dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the treatment of moderate to severe eosinophilic asthma, as determined by any means le in the art.

As used herein, forced expiratory volume in 1 second (FEV1) refers to the maximal amount of air that can forcefully be exhaled in one second.

As used herein, asthma control questionnaire (ACQ) refers to a questionnaire used to measure the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment.

As used herein, forced vital ty (FVC) refers to the volume delivered during an expiration made as forcefully and completely as possible starting from full ation.

As used herein, forced expiratory ?ow (FEF25%_75%) refers to the average forced expiratory ?ow during the mid (25 - 75%) portion of the FVC.

As used herein, asthma quality of life questionnaire (AQLQ) refers to a disease- speci?c health-related quality of life instrument that evaluates both physical and emotional impact of disease.

As used herein, asthma m utility index (AUSI) refers to a brief, interviewer—administered, patient preference—based scale assessing frequency and severity of selected asthma—related symptoms and ent side s.

As used herein, clinical asthma exacerbations (CAEs) refers to a medical intervention (either additional therapy beyond the patients usual care and/or and emergency room visit or hospital admission due to asthma) that was clinically judged (adjudicated by a committee independent of Teva) precipitated by a deterioration in lung function and/or worsening patient symptoms. l interventions that were ered as de?nitive of asthma exacerbations included either or both of: 1) use of systemic, or an se in the use of inhaled, corticosteroid treatment for 3 or more days. For patients already being treated with systemic or inhaled corticosteroids, the _ 8 _ dose of osteroids will need to be increased 2 or more fold for at least 3 or more days; and/or 2) asthma-related emergency treatment including at least 1 of: an unscheduled visit to the physician’s of?ce for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or an asthma—related hospitalization.

Disclosed herein are methods of treating moderate to severe eosinophilic asthma in a patient comprising: 1) fying a patient having moderate to severe eosinophilic asthma, wherein the patient’s symptoms are inadequately controlled with a current asthma therapeutic and wherein the patient’s blood eosinophil levels are equal to or greater than about 400/[11; and 2) administering to said patient a therapeutically effective dose of reslizumab.

Patients with eosinophilic asthma have elevated eosinophils in the lung, sputum and blood. As used herein, "moderate to severe asthma" is de?ned by a baseline medication requirement of at least medium dose d corticosteroid (for e, ICS 2 440 micrograms of ?uticasone daily dose) with or without another asthma controller. In some embodiments, for example, moderate to severe asthma can be a baseline medication requirement of at least medium dose inhaled osteroid (for example, ICS Z 440 micrograms of ?uticasone daily dose) with another asthma controller. In other embodiments, moderate to severe asthma can be a baseline medication requirement of at least medium dose inhaled corticosteroid (for example, ICS 2 440 micrograms of ?uticasone daily dose) without r asthma controller. As used herein, "moderate to severe philic asthma" is de?ned as te to severe asthma with a baseline blood eosinophil count of at least about 400/uL.

Suitable patients to be d with the disclosed methods are those whose asthma symptoms are inadequately controlled using their current asthma therapeutic. As used herein, "inadequately controlled" refers to an Asthma Control Questionnaire (ACQ) score of 2 The patient’s current therapeutic can be an inhaled corticosteroid (ICS) with or t another controller. In some embodiments, the patient’s current asthma therapeutic can se an inhaled corticosteroid without another controller. In some embodiments, the patient’s current asthma therapeutic can comprise an d osteroid with another controller. The patient’s current therapeutic can be a medium dose of inhaled corticosteroid.

For example, the inhaled corticosteroid can be at least lent to about 440 ug ?uticasone.

The patient’s current eutic can be a high dose of inhaled corticosteroid. Exemplary cut— offs for high doses of inhaled corticosteroids are provided, for example, in Table 18. In _ 9 _ embodiments wherein the patient’s current asthma therapeutic comprises an inhaled osteroid with another controller, the other controller can comprise a long acting beta 2 adrenoceptor t (LABA). In some embodiments, the patient’s current asthma eutic can comprise equal to or greater than about 440 ug ?uticasone and a long acting beta 2 ceptor agonist (LABA).

Suitable ts also include those having an elevated level of blood eosinophils. An ted level of blood eosinophils" refers to an eosinophil level that selects patients with currently active eosinophilic airway in?ammation with high speci?city. For example, an elevated level of blood eosinophils can include a higher level of blood eosinophils in the patient compared to an dual, or population of duals, that does not have asthma. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 400/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 450/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 500/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 550/ pl. In some embodiments, the t’s blood phil level can be equal to or greater than about 600/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 650/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or r than about 700/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 750/ pl.

In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 800/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 850/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 900/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or r than about 950/ pl. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 1000/ p]. In some embodiments, the patient’s blood eosinophil level can be equal to or greater than about 1500/ ul.

As used herein, "reslizumab" refers to a "humanized" (from rat) divalent monoclonal antibody (mAb) with an IgG4 kappa isotype, with binding y for a speci?c epitope on the human interleukin-5 (IL-5) molecule. Reslizumab is a lizing antibody that is believed to block IL-5 dependent cell proliferation and/or eosinophil production. Reslizumab is described in, for example, Walsh, GM (2009) "Reslizumab, a humanized anti-IL-5 mAb for the treatment of phil—mediated in?ammatory conditions" Current opinion in molecular therapeutics ll (3): 329—36; US 6,056,957 (Chou); US 6,451,982 (Chou); US RE39,548 (Bodmer), each of which is incorporated herein by reference. _ 10 _ The sequences of the heavy and light chains of reslizumab are as follows: Heavy Chain EVQLVESGGGLVQPGGSLRLSCAVSGLSLTSNSVNWIRQAPGKGLEWV (SEQ ID GLIWSNGDTDYNSAIKSRFTISRDTSKSTVYLQMNSLRAEDTAVYYCAR NO: 1) EYYGYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDMVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL Light Chain DIQMTQSPSSLSASVGDRVTITCLASEGISSYLAWYQQKPGKAPKLLIYG (SEQ ID ANSLQTGVPSRFSGSGSATDYTLTISSLQPEDFATYYCQQSYKFPNTFGQ NO:2) GTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC A therapeutically ive dose of umab can be between about 0.3 mg/kg to about 3 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 0.3 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 0.5 mg/kg. In some ments, the therapeutically ive dose of reslizumab can be about 0.7 mg/kg. In some embodiments, the eutically effective dose of reslizumab can be about 1 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 1.2 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 1.4 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 1.6 mg/kg. In some embodiments, the eutically ive dose of reslizumab can be about 1.8 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 2.0 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 2.2 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 2.4 mg/kg. In some embodiments, the therapeutically effective dose of reslizumab can be about 2.6 mgkg. In some embodiments, the therapeutically effective dose of reslizumab can be about 2.8 mg/kg. In other ments, the therapeutically effective dose of reslizumab can be about 3 mg/kg.

Numerous routes of administration are suitable including, but not limited to, intravenously (iv) or subcutaneously (sub—Q). In some embodiments, the therapeutically effective dose of reslizumab can be stered intravenously. In other embodiments, the therapeutically effective dose of reslizumab can be administered subcutaneously.

Suitable dosing schedules include, but are not limited to, one dose of a therapeutically effective dose of reslizumab once about every four weeks. In some embodiments, for example, the therapeutically effective dose of reslizumab is about 0.3 mg/kg to about 3 mg/kg administered intravenously or subcutaneously once about every 4 weeks. In some aspects, for example, the therapeutically effective dose of reslizumab is about 0.3 mg/kg stered intravenously or subcutaneously once about every 4 weeks. In some s, for example, the therapeutically effective dose of reslizumab is about 3 mg/kg administered intravenously or subcutaneously once about every 4 weeks.

Numerous criteria can be used to evaluate the ef?cacy of the disclosed methods.

Suitable efficacy determinations include, but are not limited to, the frequency of clinical asthma exacerbations (CAEs), lung function (forced expiratory volume in 1 second , forced vital capacity (PVC), and forced tory ?ow rate (FEF25%75%)), asthma quality of life onnaire score (AQLQ), asthma control questionnaire score (ACQ), time to ?rst CAE, asthma symptom score (ASUI), use of rescue inhaler, blood phil counts, or any combination thereof. In some embodiments, for example, administration of the therapeutically effective dose of reslizumab leads to an improvement in lung function, as assessed by improvements in forced expiratory volume in 1 second, forced vital capacity, forced expiratory mid-?ow rate (FEF25%_75%), or any combination thereof by about 5% or greater. For example, in some embodiments, administration of the eutically effective dose of reslizumab leads to an about 5% improvement in lung function. In some embodiments, stration of the therapeutically effective dose of reslizumab leads to an about 10% improvement in lung function. In some ments, administration of the therapeutically effective dose of reslizumab leads to an about 15% improvement in lung function. In some embodiments, administration of the therapeutically effective dose of umab leads to an about 20% improvement in lung function. In some embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 25% improvement in lung function. In some embodiments, stration of the therapeutically effective dose of reslizumab leads to an about % improvement in lung function. In some embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 35% improvement in lung function. In some embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 40% improvement in lung on. In some ments, administration of the therapeutically effective dose of reslizumab leads to an about 45% ement in lung function. In some embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 50% improvement in lung function. _ 12 _ In other embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 5% to about 50% ement in lung function. In other embodiments, administration of the therapeutically effective dose of reslizumab leads to an about % to about 50% improvement in lung function. In other embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 20% to about 50% improvement in lung function. In other embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 30% to about 50% ement in lung function. In other embodiments, administration of the therapeutically effective dose of reslizumab leads to an about 40% to about 50% improvement in lung function. stration of the therapeutically effective dose of reslizumab can lead to reduced clinical asthma exacerbations, reduced use of systemic corticosteroids, improved asthma control questionnaire score, improved asthma quality of life questionnaire score, or any combination thereof. In some aspects, the clinical asthma exacerbations can be reduced by about 50% as compared to a patient not ing umab. In other aspects, the use of systemic corticosteroids can be reduced by about 50% as compared to a patient not receiving reslizumab.

The sed methods can be used to treat a patient having late—onset asthma. ingly, in some embodiments the methods of treating moderate to severe eosinophilic asthma in a patient can comprise: 1) identifying a patient having moderate to severe eosinophilic asthma, wherein the patient’s symptoms are inadequately controlled with a t asthma therapeutic, wherein the patient’s blood eosinophil levels are equal to or greater than about 400/[11, and wherein the patient has late—onset asthma; and 2) stering to said patient a therapeutically effective dose of reslizumab.

As used , "late—onset asthma" refers to an asthma diagnosis in a patient that is 40 years old or older at the time of initial diagnosis. stration of the therapeutically effective dose of reslizumab to a t having late—onset asthma can lead to an improvement in lung function compared to a patient not receiving reslizumab. In some ments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 90 ml change in forced expiratory volume in 1 second (AFEVI) compared to a patient not receiving reslizumab.

In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late—onset asthma leads to greater than about 105 ml change in forced tory volume in 1 second ) compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 125 ml change in forced expiratory volume _ 13 _ in 1 second (AFEVl) compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a t having late-onset asthma leads to greater than about 135 ml change in AFEV1 compared to a patient not receiving umab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 145 ml change in AFEV1 compared to a patient not receiving reslizumab. In some embodiments, administration of the eutically effective dose of umab to a patient having late—onset asthma leads to r than about 155 ml change in AFEV1 compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a t having late-onset asthma leads to greater than about 165 ml change in AFEV1 ed to a patient not ing reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 175 ml change in AFEV1 compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 190 ml change in forced tory volume in 1 second (AFEVl) compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 205 ml change in forced expiratory volume in 1 second (AFEVl) compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically ive dose of reslizumab to a patient having late-onset asthma leads to greater than about 220 ml change in forced expiratory volume in 1 second (AFEVl) ed to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a patient having late—onset asthma leads to greater than about 235 ml change in forced expiratory volume in 1 second (AFEVl) compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically ive dose of reslizumab to a patient having late-onset asthma leads to greater than about 245 ml change in forced expiratory volume in 1 second ) compared to a patient not receiving reslizumab.

Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to an about 90 ml to about 250 ml change in AFEV1 compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a t having late—onset asthma can lead to an about 125 ml to about 250 ml change in AFEV1 compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to an about 150 ml to about 250 ml change in AFEV1 compared to a t not ing reslizumab. _ 14 _ Administration of the therapeutically effective dose of reslizumab to a t having late-onset asthma can lead to an about 175 ml to about 250 ml change in AFEV1 compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a t having late-onset asthma can lead to an about 200 ml to about 250 ml change in AFEV1 compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of umab to a patient having late—onset asthma can lead to an about 90 ml to about 200 ml change in AFEV1 compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to an about 90 ml to about 175 ml change in AFEV1 ed to a patient not receiving reslizumab.

Administration of the therapeutically effective dose of reslizumab to a t having late-onset asthma can lead to an about 90 ml to about 150 ml change in AFEV1 compared to a patient not ing reslizumab. Administration of the therapeutically effective dose of umab to a patient having late-onset asthma can lead to an about 90 ml to about 125 ml change in AFEV1 compared to a patient not ing reslizumab.

Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to a reduction of clinical asthma exacerbations ed to a patient not receiving reslizumab. In some aspects, stration of the therapeutically effective dose of reslizumab to a patient having late—onset asthma leads to an about 50% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab. In some aspects, administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma leads to greater than about 50% reduction in clinical asthma exacerbations compared to a t not receiving reslizumab. For example, administration of the therapeutically effective dose of reslizumab to a patient having late—onset asthma can lead to a 50% reduction in clinical asthma exacerbations compared to a patient not ing reslizumab. stration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to a 55% ion in clinical asthma exacerbations compared to a t not receiving reslizumab. stration of the therapeutically effective dose of reslizumab to a patient having late—onset asthma can lead to a 60% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to a 65% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab. Administration of the therapeutically ive dose of reslizumab to a patient having late—onset asthma can lead to a 70% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab. Administration of the therapeutically effective dose of reslizumab to a patient having late-onset asthma can lead to a _ 15 _ 75% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab.

Administration of the therapeutically effective dose of umab to a patient having late-onset asthma can lead to a 80% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab. In some embodiments, administration of the therapeutically effective dose of reslizumab to a t having late—onset asthma leads to an about 50% to about 80% reduction in clinical asthma exacerbations compared to a patient not ing reslizumab. In some embodiments, administration of the eutically effective dose of reslizumab to a patient having late-onset asthma leads to an about 60% to about 75% reduction in clinical asthma exacerbations compared to a patient not receiving umab. In some embodiments, administration of the eutically effective dose of reslizumab to a patient having late-onset asthma leads to an about 70% to about 80% reduction in clinical asthma exacerbations compared to a patient not receiving reslizumab.

EXAMPLES Exam 1e 1: Stud 1 —treatment with lacebo umab 0.3 m /k or reslizumab 3.0 m k once eve 4 weeks for a total of 4 doses 16 weeks Studies were conducted to determine whether reslizumab, at a dosage of 0.3 mg/kg or 3.0 mg/kg administered once every 4 weeks for a total of 4 doses, is more effective than o in improving pulmonary function and asthma control in asthma patients with elevated eosinophil levels.

Study Design A global Phase 3, enter, randomized, double—blind, placebo—controlled, parallel-group, ?xed dosage study was performed to compare the ef?cacy and safety of umab (RES) vs placebo (PBO) in subjects with moderate to severe, persistent asthma with elevated eosinophil levels. Eligible subjects were randomized (1 : 1 : 1) to receive placebo, reslizumab 0.3 mg/kg, or reslizumab 3.0 mg/kg stered once every 4 weeks for a total of 4 doses. Subjects had the option to enroll in an open-label extension study after completing the 16-week double-blind treatment period.

Eligible subjects were between the ages of 12 and 75 and had moderate to severe asthma based on prior medication requirement: 2440 pg per day of ?uticasone or _ 16 _ equivalent :: another controller (e.g., LABA). The asthma had to be inadequately controlled based on an Asthma Control Questionnaire (ACQ) score of 21.5. Subjects were required to have a baseline blood eosinophil count of 2400/nL. There was no speci?c forced expiratory volume in 1 second (FEVl) or asthma exacerbation ion.

Outcome Variables The primary ef?cacy variable was the change from ne in FEVl.

Secondary ef?cacy variables included: ACQ score (the self-administered portion of the ACQ-7 consists of 5 items scoring ms and 1 item scoring rescue medication use, as well as other lung function (FEV1 measurements ted in the clinic; forced vital capacity (FVC); forced tory ?ow 25—75% (FEF25_75%); asthma quality of life questionnaire ; asthma symptoms (via the ASUI tool); use of reliever short acting beta t (SABA); and safety (adverse events).

Statistics The ef?cacy analyses were based on the full analysis set (all randomized patients who were treated with at least 1 dose of study drug) and treatment group as randomized.

Ef?cacy variables were analyzed using mixed model repeated measures (MMRM) with ?xed effects (treatment, strati?cation factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the block factor for the repeated measurements. An unstructured covariance matrix was used for within—patient correlation modeling. The overall ent effect for each reslizumab dose was compared with o using a 2—sided test at the signi?cance level of 0.05. A strati?ed Cochran-Mantel-Haenszel (CMH) test was used to analyze the tion of patients achieving at least a 05-point reduction in ACQ.

Results Of the 1025 subjects who were screened, 315 met eligibility criteria and were randomized. Of the 315 patients who were randomized, 268 (85%) completed the study (81%, 89%, and 85% in the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg groups, respectively). Overall, the most common reason for discontinuation was e events (n=19 overall; n=ll placebo; n=l reslizumab 0.3 mg/kg; n=?' umab 3.0 mg/kg), followed by withdrawn consent (n=7 overall; n=2 placebo; n=l reslizumab 0.3 mg/kg; n=4 reslizumab 3.0 mg/kg), lack of ef?cacy (n=6 overall; n=2 placebo; n=3 reslizumab 0.3 _ 17 _ mg/kg; n=1 reslizumab 3.0 mg/kg), and protocol ion (n=6 overall; n=2 placebo; n=3 reslizumab 0.3 mg/kg; n=1 reslizumab 3.0 mg/kg). The full analysis set and the safety population included 311 subjects (placebo: n=105; reslizumab 0.3 mg/kg: n=103; reslizumab 3.0 mg/kg: n=103). Results are based on the full analysis set, unless otherwise speci?ed. Baseline t demographics and disease characteristics are summarized in Tables 1 and 2.

Table 1 1217neC%) 44.2 44.5 43 56) 56) 5o) FVDI(96) 59/41 57443 58/42 Race (%) rema1n1ng Non—hispanic non-latino Hispanic or Latino BMI (kg/m2) 27.7 27.6 27.4 27.6 Table 2 ITICS C6 rEXAC prior 12 mo ? YES % Reversibility FEV1 (L) FEV1 % ————— Rescue use 2.3 1.9 2.3 (puff/day Blood EOS X 0.6 (0.1— 3.7) 0.6 (0.1—3.7) 0.6 0.6(0—1.6) 109’L (range) % on a LABA* *Long acting beta agonist: not speci?cally programmed Changefrom Baseline in FE V1 The is of the primary ef?cacy variable, overall change from baseline in FEV1 over 16 weeks of treatment (obtained from the MMRM estimation) showed signi?cant improvement (increase) in FEV1 for patients in both umab treatment groups compared with placebo (Table 3). The overall change from ne in FEV1 was 0.126 L, 0.242 L, and 0.286 L for the patients in the placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab treatment groups, respectively. The overall treatment effect was larger for patients in the umab 3.0 mg/kg treatment group (0.160 L, p=0.0018) than for patients in the reslizumab 0.3 mg/kg treatment group (0.115 L, p=0.023 7).

The treatment effect for change in FEV1 from baseline to weeks 4, 8, l2, l6, and endpoint for patients in the 0.3 mg/kg and 3.0 mg/kg reslizumab treatment groups were analyzed secondarily (Figure l and Table 3). A treatment effect in FEV1 was seen after the ?rst dose of 3.0 mg/kg reslizumab at the ?rst led 4—week assessment (0.153 L, p=0.003) that was sustained at the 16—week ment (0.165 L, p=0.0118). Improvements for ts in the 0.3 mg/kg reslizumab treatment group were more variable, but numerically greater than those for patients in the placebo ent group at every clinic visit.

Substantial placebo effects are not unexpected given that ts were allowed to continue SoC TX and likely become more compliant during the study. Signi?cant improvements in FEV1 were observed in subjects as early as 4 weeks after treatment with reslizumab 3.0 mg/kg compared with placebo (treatment difference: 153 m1, P=0.003 and maintained over the duration of the study.

Table 3 ————— ————— ————— Change in nat) 103 101 102 FEVl (liters) Over 16 Weeks —SEofLSmean 0.0549 0.0556 0.0548 Treatment 0.1 15 0.160 difference (active - placebo) SE of difference 0.0508 0.0507 95% CI , 0.215) (0.060, 0.259) p-value 0.0237 0.0018 Week 16 change 1’1 oo.1; \oN G,_. in FEVI s) Mean 0.052 0.188 0.243 U) 0.3944 0.5568 0.4782 SE of mean 0.0430 0.0581 0.0501 Median 0.000 0.105 0.170 Min, max —0.760, 1.430 —l.080, 2.670 —0.890, 1.970 LS mean 0.137 0.266 0.302 SE of LS mean 0.0622 0.0624 0.0616 Treatment 0.129 0.165 difference (Active - Placebo) SE of ence 0.0651 0.0651 95% CI (0.001, 0.257) (0.037, 0.293) p-value 0.0481 0.0118 a)n denotes number of patients who contributed at least once to the analysis.

FEV1= forced expiratory volume in 1 second; SD= standard deviation; SE= standard error; min=minimum; max=maximum; LS=Least Squares; CI: con?dence interval Note: Endpoint=Week 16 or early withdrawal.

Changefrom Baseline in FVC by Visit The overall change from baseline in FVC over 16 weeks of treatment showed improvement (increase) in the umab 3.0 mg/kg treatment group compared with placebo (0.130 L, p=0.0174) (Table 4). The overall treatment effect for the 0.3 mg/kg reslizumab group compared with o was 0.048 L (p=0.3731). Improvement in FVC by visit was observed for patients in the reslizumab 3.0 mg/kg treatment group by 8 weeks after the second dose of reslizumab (0.153 L, p=0.0190) that was sustained hout the 16 week ent period.

Improvements for patients in the reslizumab 0.3 mg/kg treatment group were numerically greater than placebo at every clinic visit (Figure 2).

Table 4 Placebo (N=105) Baseline FVC 3.288 3.289 3.199 (AU 1.0503 1.1232 1.0097 SE of mean 0.1025 0.1107 0.0995 Median 3.200 3.230 3.020 Min, max 0.880, 6.180 1.290, 6.010 0.660, 5.640 Overall change in na) 103 101 102 LS mean 0.172 0.220 0.301 SE of LS mean 0.0614 0.0623 0.0613 Treatment 0.048 0.130 difference (active - placebo) SE of difference 0.0543 0.0543 95% CI (-0.058, 0.155) (0.023, 0.237) p-value 0.3731 0.0174 Week 16 change 11 00 \0 in FVC LS mean 0.201 SE of LS mean 0.0678 difference (Active — Placebo) SE of difference 0.0675 0.0676 95% CI (-0.101, 0.165) (-0.019, 0.247) 21)n denotes number of patients who contributed at least once to the analysis.

SD= standard deviation; SE= standard error; nimum; max=maximum; LS=Least Squares; CI= con?dence al.

Changefrom Baseline in FEF25%75% by Visit The overall LS mean change from baseline in FEF25%_75% over 16 weeks of treatment was numerically improved for patients in the reslizumab 3.0 mg/kg treatment group compared with placebo (0.233 L/second, p=0.0552). The overall treatment effect for the 0.3 mg/kg reslizumab ent group was small (0.030 L/second, p=0.8020) (Table 5). Treatment differences were not sizable for either reslizumab treatment group compared with placebo at any of the 4—week Visits following week 4 (Figure 3).

Table 5 Baseline 1.657 2.337 1.705 FEF25%-75% mU 0.9201 8.9642 1.5396 SE of mean 0.0898 0.8833 0.1517 Median 1.510 1.250 1.450 Min, max 0.270, 4.370 0.210, 92.000 0.360, 14.600 Overall change in n" 103 101 102 FEF25%-75% LS mean —0.145 —0.114 0.089 SE of LS mean 0.1342 0.1361 0.1342 Treatment 0.030 0.233 (active - placebo) SE of difference 0.1215 0.1212 95% CI (-0.209, 0.270) (0005, 0.472) e 0.8020 0.0552 Week 16 change n 00A K)N in FEF25%-75% LS mean Treatment 0.052 0.216 difference (Active - Placebo) —SEofdifference — 0.1276 0.1276 —95%CI — (0199,0303) (-0035, 0.468) 21)n denotes number of patients who contributed at least once to the analysis. _75%= forced expiratory ?ow at 25% to 75% forced vital capacity; SD=standard deviation; SE= rd error; min=minimum; max=maximum; LS=Least Squares; CI= con?dence interval Overall Changefrom Baseline in FE V; Subpopulation (FEV; % Predicted 385%) No specific baseline FEV1 inclusion criterion was mandated for this study.

Therefore, a secondary analysis obtained from the MMRM tion, was performed for the y efficacy variable for patients included in the FEV1 FAS with % predicted FEV1 585% at baseline to gain insight around ef?cacy in patients with more impaired lung function (i.e., FEV1 subpopulation). The overall change from baseline in FEV1 by subpopulation is was 0.199 L, 0.285 L, and 0.364 L for the ts in the placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab treatment groups, respectively. Results showed cal improvement in FEV1 for both reslizumab treatment groups compared with placebo (Table 6); however, significant improvement was only observed for the reslizumab 3.0 mg/kg treatment group (treatment difference 0.165 L, p=0.0066) (Figure 4). Of note, this analysis was performed on a smaller tion for which the study was not powered.

Table 6 Overall change in a) 79 84 8 1 FEV1 (liters) Treatment 0.087 0.165 difference (active - placebo) ifference — 0.0597 0.0603 —95%CI —(—0.031, 0.204) (0046,0284) Changefrom Baseline in Asthma Controz’ Questionnaire The analysis overall mean change from baseline in ACQ score over 16 weeks of treatment showed improvement (decrease) for ts in the reslizumab 0.3 mg/kg and 3.0 mg/kg ent groups compared with placebo (-0.238 units, p=0.0329 and -0.359 units, p=0.0014, respectively) (Table 7). The ent effect for change in ACQ from baseline to weeks 4, 8, l2, and 16 for the 0.3 mg/kg and 3.0 mg/kg reslizumab treatment groups was also analyzed (Figure 5). Improvement in ACQ was seen after the first dose of umab 3.0 mg/kg at the ?rst scheduled 4—week assessment (p = 0.0153) which was sustained throughout the k treatment period. Improvements for patients in the reslizumab 0.3 mg/kg treatment group were more variable, but numerically greater than o at every clinic visit.

Improvement in ACQ scores at 16 weeks was observed for the 3 mg/kg but not for the 0.3 mg/kg dose level (p=0.0129 and p=0.l327, respectively).

In an analysis of subjects remaining in the trial at each visit, the proportion of subjects that achieved the minimal clinically ant difference in ACQ score (0.5 units) was signi?cantly greater with either dose of reslizumab (51—59%) compared with placebo (3 7%) at week 4 (Figure 6). Numeric differences observed versus placebo at later visits were not signi?cant, noting that placebo results improved over time as a disproportionate number of placebo subjects withdrew from the study.

Table 7 Baseline ACQ Mean 2.471 2.499 2.591 score ————— ————— ————— ————— —SEofLSmean 0.1231 0.1250 0.1233 Treatment —0.238 -0.359 difference (active - placebo) ifference — 0.1108 0.1110 —95%CI —(-0.456, -0.019) (-0.577, 0140) Week 16 change na) 84 92 91 in ACQ score Treatment -0.211 -0.351 (active - placebo) ifference — 0.1399 0.1402 a)n denotes number of patients who contributed at least once to the analysis.

SD= standard deviation; SE: standard error; min=minimum; ximum; LS=Least Squares; CI= con?dence interval Changefrom Baseline to Week 16 in Asthma Quality ofLife Questionnaire The AQLQ assesses the effect of reslizumab on quality of life metrics including overall activity, asthma symptoms, emotional function, and response to environmental stimuli.

The AQLQ score was only assessed once during the study at week 16 or at early withdrawal if it met endpoint criteria for y assessments: i.e., last post—baseline assessment if within 3 to 5 weeks of the last dose of study drug. A treatment difference was observed in AQLQ total score ed with placebo for the 3.0 mg/kg reslizumab treatment group (0.359 units, p=0.0241); (Figure 7 and Table 8). AQLQ scores for the subdomains of asthma symptoms and emotional function scores were also ed (increased) for the reslizumab 0.3 mg/kg and 3.0 mg/kg treatment groups compared with placebo. The proportion of patients achieving at least 0.5 improvement from baseline to week 16 in AQLQ (Figure ?B).

Table 8 —-———totalscore ————— ————— ————— ————— Week 16 change in AQLQ total score —SEofLSmean 0.1817 0.1881 0.1829 Treatment 0.278 0.359 (active - o) —SEofdiffem _oml 0.1582 a)n denotes number of patients who contributed at least once to the analysis.

SD= standard deviation; SE: standard error; min=minimum; max=maximum; LS=Least Squares; C1= con?dence interval.

Changefrom Baseline in Asthma m Utility Index by Visit The overall LS mean change from baseline in ASUI (scores range from 0 [worst possible symptoms] to 1 [no ms]) over the 16 weeks of treatment was improved (increased) ed with placebo for the 0.3 mg/kg (0.051 units, p=0.0094) and 3.0 mg/kg (0.047 units, p=0.0160) reslizumab treatment groups (Table 9) (Figure 8). This indicates that the patients in the reslizumab treatment groups had less frequent and less severe asthma related symptoms than patients treated with placebo, although the l difference did not reach the minimal ant difference (MID) of the ASUI, which has recently been determined to be 0.09 (Bime et a1 2012).

Improvement in asthma related symptoms was seen at the ?rst scheduled 4 week assessment (p50.05) after the ?rst dose of reslizumab 0.3 mg/kg and 3.0 mg/kg that was generally sustained throughout the 16 week treatment period (Figure 8).

Table 9 Baseline ASUI Mean 0.674 0.675 0.657 score ————— ————— ————— ————— ASUI score ————— ————— Treatment 0.051 0.047 (active - placebo) Week 16 change na) 84 93 91 in ASUI score Treatment 0.040 0.040 difference (active - placebo) ifference —0.0257 0.0258 —95%CI —(—0.010, 0.091) (—0.011,0.091) 21)n denotes number of patients who contributed at least once to the analysis.

SD= standard deviation; SE= standard error; min=minimum; max=maximum; LS=Least Squares; CI= con?dence interval.

Changefrom Baseline in Short Acting Beta Agonist (SABA) Use by Visit During each scheduled visit, patients were asked to recall the total number of puffs of SABA they used over the 3 days prior to each scheduled clinic visit. There was an overall ion in daily SABA use (number of puffs per day) for the 0.3 mg/kg and 3.0 mg/kg reslizumab treatment groups compared with the placebo treatment group over 16 weeks of treatment ( 1.0 puff/day, p=0.0119 and 0.9 puff/day, p=0.0151, respectively) (Table 10, Figure 9). Compared to placebo treated patients, a se in rescue SABA ement was observed for reslizumab treated ts by the ?rst assessment at week 4 and was sustained through week Table 10 Baseline averag daily SABA use Nu: [\J DJ SE of mean Median .NO >—‘ \1 Min, max Overall change in na average daily SABA use (#puffs/day) LS mean 3: U.) -1 .0 ————— Treatment -0.648 -0.624 difference (active - placebo) Week 16 change na) 83 93 91 in average daily SABA use (#puffs/day) ————_ ————— Treatment —0.648 -0.708 (active — placebo) —SEofdifference —0.3200 0.3201 —95%CI —(-1.278,-0.017) (4.339, —0.077) 21)n denotes number of ts who contributed at least once to the analysis.

SD: standard deviation; SE: standard error; min=minimum; max=maximum; st Squares; CI= con?dence interval.

Changefrom Baseline in Blood Eosinophi! Count Overall change from baseline in blood eosinophil count (109/L) over the 16 weeks of treatment showed treatment differences (reductions in blood eosinophil count) for the 0.3 mg/kg (p=0.0000) and 3.0 mg/kg (p=0.0000) reslizumab treatment groups compared with placebo, which were st for the 3.0 mg/kg group (Table 11, Figure 10).

Table 11 Baseline Mean 0.601 0.644 0.595 Eosinophil Count (109/L) ————— ————— ————— Overall change1n na) phil Count (109/L) Treatment 0323 -0.494 difference (active - placebo) —SEofdifference —( 0.0243 0.0242 Week 16 change in Eosinophil Count (109/L) Treatment —0.320 -0.460 difference (active - placebo) —SEofdifference — 0.0320 0.0322 —95%CI —(—0.383, 0.257) (0.523, -0.396) 3)n s number of patients who contributed at least once to the is.

SD= standard deviation; SE= standard error; min=minimum; max=maximum; LS=Least Squares; CI= con?dence interval.

Treatment differences were also observed for both the 0.3 mg/kg and 3.0 mg/kg reslizumab ent groups ed with o at each independent visit (weeks 4, 8, 12, and 16) (p=0.0000, all comparisons). As the vast majority of treated patients either elected to continue on to Study C3 8072/3085 open label ion after completing treatment at week 16 (86%), or failed to provide follow up for other reasons, the blood eosinophil data for the 90 day follow-up visit (6, 9, and 8 patients in the placebo, 0.3 mg/kg and 3 mg/kg treatment groups, respectively), were very limited. The mean changes in blood eosinophil counts from baseline to the follow up visit were —0. 197 x 109/L, 0.119 x 109/L, and 0.133 x 109/L for patients in the placebo, 0.3 mg/kg reslizumab group, and 3.0 mg/kg reslizumab group, respectively. These limited data indicate that blood eosinophils in both reslizumab groups returned to baseline by the follow up visit (i.e., approximately 4 months after the last dose of reslizumab).

Eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), and eosinophil peroxidase (EP) present in serum and plasma were characterized as potential biomarkers. ECP and EDN, indicators of eosinophilic in?ammation, may aid clinicians in the diagnosis, treatment, and monitoring of their patients with asthma (Kim 2013). Serum concentrations of ECP and EDN are ted in Table 12. The EP analyses were not performed due to the unavailability of a le, robust method.

All available ECP and EDN data were included for evaluation and missing or invalid results were not ted for the biomarker analyses. The biomarker es included only patients in the FAS who had blood samples drawn for the determination of biomarkers.

Twelve biomarker measurements obtained from 5 patients (422102, placebo; 004112 and 181102, 0.3 mg/kg reslizumab; 019136 and 504113, 3.0 mg/kg reslizumab) were ed due to a missing date of a post screening led visit.

Serum ECP and EDN levels were similar in patients in all 3 study groups at baseline. From baseline to week 16, both ker levels remained about the same in patients in the o group, decreased slightly in patients treated with 0.3 mg/kg reslizumab, and decreased the most in patients treated with 3.0 mg/kg reslizumab (Table 12). The percentage decreases in serum ECP levels from baseline to week 16 were 8.5%, 52.0%, and 74.1% in the placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab , respectively. The percentage decreases in serum EDN levels from baseline to week 16 were 6.3%, 51.4%, and 73.9% in the placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab groups, respectively. The mean changes from baseline in serum levels of ECP and EDN are represented graphically in Figure 11A and Figure 11B, respectively.

Table 12 Serum Baseline 103 100 100 ECP (ng/mL) 88.2 92.7 94.6 SD 98.09 93.27 114.87 SE of mean 9.67 9.33 11.49 Median 58.7 64.4 61.6 Min, max 4.0, 675.1 4.0, 728.3 4.1, 694.3 Week 16 n 93 94 94 —————— —————— —————— —————— Serum Baseline na) 103 100 100 EDN (ng/mL) —————— —————— —————— —Weem —————— —————— —————— —————— —————— 8)n denotes number of patients who contributed at least once to the analysis.

SD= standard deviation; SE: standard error; min=minimum; max=maximum.

Adverse Events The most common e events were asthma, headache, nasopharyngitis, upper respiratory tract ion, and sinusitis (Table 13). Serious adverse events included: acute myocardial infarction (n=l; placebo); pneumonia (n=l; umab 3.0 mg/kg) occurred 11 days after the first dose of reslizumab, patient discontinued (during the 90-day follow—up in same patient: road traffic accident; rib fracture; asthma exacerbation); sinusitis (n=l; reslizumab 3.0 mg/kg); and asthma (n=2; reslizumab 3.0 mg/kg). No deaths ed during the study.

Table 13 2 1 AE, ANY 66 (63) 59 (57) 61 (59) 1<<1> — 4(4) Adverse events in > 2% of subjects in any reslizumab group (preferred term) 2m 66 w 66 86> new Nasopharyngitis 4 (4) 6 (6) 6 (6) tract infection 3m 3m 4(4) (5) 5(5) 2(2) 4(4) 4(4) 1<<1> Pharyngitis 3 (3) 3 (3) 1 (<1) Musculoskeletal and 4 (4) 3 (3) 7 (7) connective tissue1 Nervous system 11 (10) 10 (10) 16 (16) disorders2 1 3 mg/group accrued additional cases (< 1% each) of arthralgia, joint stiffness, oskeletal chest pain, Myalgia, and tendonitis. 2 Primarily ted for by additional headaches: PBO, 0.3 and 3 mg/kg at 6, 8 % and 11% respectively.

The frequency of l AEs were essentially balanced across SOCs excepting.

Treatment-related AE (as assessed by investigator): the slight excess in ent related AE seen in the reslizumab 3 mg/kg group (12%) vs. placebo (8%) was generally related to accrual of single AEs (incidence < 1%) across multiple SOCs without apparent pattern. Serious AE for reslizumab all occurred in the 3 mg/kg dose; none related. Same patient: 1 each - pneumonia; road accident/rib fracture; asthma bation — not related; 1 sinusitis — not related; 2 asthma exacerbation — not related. Discontinuation AEs for reslizumab included asthma (4), myalgia (1) and pneumonia (1). Conclusion: No speci?c safety concerns. The topline safety results for 3081 are consistent with the known safety pro?le for reslizumab Conclusion In subjects with ed blood eosinophils, 4 monthly doses of reslizumab were well tolerated and associated with ements in pulmonary function and patient-reported asthma control on top of rd—of—care therapies. Primary efficacy was met for both 0.3 mg/kg and 3 mg/kg. However, improvements were generally larger for the 3 mg/kg dose, and met statistical signi?cance, for all clinically important metrics. Reslizumab onset of action occurred within one month across both lung function and patient-centric es. The 3 mg/kg dose produced a r effect on blood phil lowering than the 0.3 mg/kg dose.

Example 2: Studies 2 and 3 — treatment with placebo or reslizumab 3.0 mg/kg once evem 4 weeks for a total of 13 doses 152 weeks: Study Drugs Study drugs were provided as sterile solutions for infusion. Reslizumab was presented as 100 milligrams (10 milliliters) per vial, ated at 10 milligrams per milliliter in millimolar sodium acetate, 7% sucrose, and pH 5.5 buffer. Placebo was presented as 10 milliliters per vial, formulated in 20 millimolar sodium acetate, 7% sucrose, and pH 5.5 buffer.

Both study drugs were added and mixed with sterile saline for infusion and then administered via an intravenous infusion line out?tted with a sterile, non—pyrogenic infusion, single—use, low— protein binding ?lter (0.20 to l micrometer in diameter). Prior to use, reslizumab and placebo were stored in a erator at a controlled temperature (2° to 8° Celsius).

Inclusion and Exclusion criteria and Patients Two duplicate randomized, double—blind, placebo—controlled, parallel-group trials (studies 2 and 3) were conducted.

Patients enrolled in either study had to meet the following inclusion criteria: ° Male or female patients aged 12 to 75 years with a previous diagnosis of ; ° At least one asthma bation requiring oral, uscular, or intravenous corticosteroid use for 2 3 days over the past 12 months before screening; ° t blood eosinophil level of 2 400 per iter (at screening); ° Airway reversibility of 2 12% to beta—agonist administration (airway reversibility was demonstrated by withholding long—acting gonist (LABA) therapy for 2 12 hours and short—acting beta-agonist therapy (SABA) for 2 6 hours before measuring forced expiratory volume in 1 second (FEVl), and then repeating the FEV1 measurement after receiving SABA therapy (up to four puffs). If a patient’s FEV1 improved by 2 12% between the two tests, the patient was deemed as having airway reversibility. One retest was permitted during the ing period); ' Asthma Control Questionnaire (ACQ) score of 2 1.5 at screening and at baseline (before the first dose of study drug); ° Use of inhaled ?uticasone at a dosage of Z 440 micrograms, or equivalent, daily chronic oral corticosteroid use (S 10 milligrams per day of sone or equivalent) was allowed. If a t was on a stable dose (e.g. 2 2 weeks of oral corticosteroid treatment) at the time of enrollment, the patient had to remain on this dose throughout the study.

The patient’s baseline asthma therapy regimen (including, but not limited to, inhaled corticosteroids, oral corticosteroids [up to a maximum dose of 10 milligrams of prednisone daily or equivalent], leukotriene antagonists, 5—1ipoxygenase inhibitors, or cromolyn sodium) had to be stable for 30 days prior to screening and baseline, and had to continue without dosage s throughout the study); ° All female patients had to be surgically sterile, 2 years postmenopausal, or have a ve uman chorionic gonadotropin (B—HCG) pregnancy test at screening (serum) and at ne (urine); ' Female patients of childbearing potential (not surgically sterile or 2 years nopausal) had to use a medically accepted method of contraception and agree to continued use of this method for the duration of the study and for 30 days after completing the trial (acceptable methods of ception included the barrier method with spermicide, abstinence, an terine device (IUD), and dal contraceptives (oral, transdermal, implanted, or ed). Partner sterility alone was not acceptable for inclusion); ° Provision of written informed consent (patients aged 12 to 17 years had to provide assent); ° Reasonable health (except for the diagnosis of asthma), as judged by the investigator, and as determined by a medical history, medical ation, electrocardiogram evaluation (at screening), and serum chemistry, hematology, and urinalysis; ° Willing and able to understand and comply with study restrictions, requirements, and procedures, as speci?ed by the study center, and to remain at the study center for the required duration during the study period, and be willing to return to the center for the -up evaluation as speci?ed in the protocol; and ° Patients who experienced an asthma bation during the screening period were considered to have failed screening and were not randomized to study treatment (patients could only be rescreened once).

Patients who met any of the following criteria were excluded from the studies: Any clinically meaningful comorbidity that could interfere with the study schedule or procedures, or compromise safety; Known hypereosinophilic syndrome; Another confounding _ 35 _ underlying lung disorder (e. g. chronic obstructive pulmonary disease, pulmonary ?brosis, or lung cancer) (Patients with pulmonary conditions with symptoms of asthma and blood philia (e. g. Churg-Strauss syndrome or allergic bronchopulmonary aspergillosis) were excluded); Current smoker (i.e. had smoked within the last 6 months prior to screening); Current use of systemic suppressive, immunomodulating, or other biologic agents ding, but not limited to, mmunoglobulin E monoclonal antibodies, methotrexate, cyclosporine, interferon—0t, or anti-tumor necrosis factor [anti—TNF] monoclonal antibodies) within 6 months prior to screening; Prior use of an anti-human interleukin-5 monoclonal antibody (e. g. reslizumab, mepolizumab, or benralizumab); Any inadequately controlled, aggravating medical s (e. g. rhinitis, gastro-esophageal re?ux disease, or rolled diabetes); Participation in any investigative drug or device study within 30 days prior to screening, or any investigative biologics study within 6 months prior to screening; Female patients who were pregnant, nursing, or, if of childbearing potential, not using a medically accepted effective method of birth control (e.g. barrier method with spermicide, abstinence, IUD, or steroidal contraceptive [oral, transdermal, implanted, or inj ected]); Concurrent infection or disease that prevented assessment of active asthma; History of concurrent immunode?ciency (human immunode?ciency virus [HIV], acquired immunode?ciency syndrome [AIDS], or congenital immunode?ciency); Current ted drug and alcohol abuse, as ed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision V-TR); Active parasitic infection within 6 months prior to ing; Receipt of any live attenuated e within the 12-week period prior to screening; History of allergic reactions to or hypersensitivity to any component of the study drug; An infection within 4 weeks prior to screening or during the screening period necessitating admission to hospital for 2 24 hours, or treatment with intravenous or oral antibiotics; History of exposure to water—borne parasites within 6 weeks prior to screening or during the screening period, or a history of diarrheal illness of rmined etiology within 3 months prior to screening or during the ing period; and Requirement for treatment for an asthma exacerbation within 4 weeks of screening or during the screening period.

Treatment Patients were strati?ed by regular maintenance oral osteroid use at enrollment (‘yes’ versus ‘no’) and by region (‘United States’ versus ‘Other’), and randomized 1:1 to receive an intravenous infusion of reslizumab 3 mg/kg or matching o, every 4 weeks (13 doses; last dose on week 48). Randomization was performed using interactive se technology with computerized central randomization. Study drugs (discussed above) were _ 36 _ provided by the sponsor. Patients were required to continue their usual asthma treatment, ing but not limited to, long-acting beta agonists (LABA), inhaled corticosteroids (ICS), OCS (:10 mg per day of prednisone or lent), leukotriene rs, and cromolyn sodium, at constant doses. Treatments were required to be stable for 30 days prior to screening.

Endpoints and ments The ef?cacy, safety and immunogenicity of reslizumab treatment for adolescent and adult ts with eosinophilic asthma whose symptoms are inadequately lled with inhaled corticosteroids were evaluated. Primary ef?cacy was determined by the annual frequency of clinical asthma exacerbations (CAE), with events adjudicated by an independent review tee. CAE were defined as worsening of asthma resulting in use of systemic corticosteroids in patients not already receiving treatment, or a two-fold increase in the dose of either ICS or systemic corticosteroids for 23 days, and/or the need for asthma—related ncy treatment (emergency room visit, hospitalization, or unscheduled physician’s of?ce visit for nebulizer or other urgent treatment). The per protocol de?nition of exacerbations were that they were ed to be associated with 21 of the following: decrease in FEV1 of 220% from baseline; ion in peak expiratory ?ow rate by 230% from baseline on 2 consecutive days; or ing signs or symptoms per physician evaluation. Patients experiencing an exacerbation could continue in the study after receiving appropriate medical therapy, unless otherwise decided by the principal igator.

Secondary ef?cacy determinations included lung function (Forced Expiratory Volume in 1 second (FEV1), Asthma Quality of Life Questionnaire (AQLQ) total score, Asthma Control Questionnaire (ACQ-7) score, Asthma Symptom Utility Index (ASUI) score, time to ?rst CAE, rescue use of short—acting beta—agonist (SABA), blood eosinophil count, Forced Vital Capacity (FVC), and Forced Expiratory Flow Rate %,75%)). SABA use was based on patient recall of treatment used in the 3 days prior to each visit. Blood eosinophil counts were measured using a standard complete blood count with ential blood test: the results of the differential were redacted after initiation of treatment to ensure the integrity of the double blinding was maintained. Additional secondary endpoints included safety (based on assessment of adverse events, tory tests, vital signs, electrocardiography, physical examinations, and concomitant medication use) and immunogenicity.

Prebronchodilator spirometry, ASUI and ACQ scores, SABA use, blood phil count, and safety parameters were assessed every 4 weeks. AQLQ score was evaluated at baseline, and at weeks 16, 32, and 52/early withdrawal. Anti-reslizumab antibodies _ 37 _ were measured at weeks 16, 32, and 52/early withdrawal, and also in any patient experiencing a serious adverse event, adverse event leading to discontinuation, or al asthma exacerbation.

Statistical analyses Ef?cacy endpoints were evaluated in the intention-to-treat population (all randomized patients) and safety endpoints were assessed in the safety population (all patients receiving :1 dose of study medication). bation frequency (primary endpoint) was analyzed using a negative binomial regression model, including treatment arm and randomization strati?cation factors as model factors, and logarithm of follow-up time excluding the summed duration of exacerbations in the treatment period as an offset le. Rate ratios versus placebo and 95% con?dence intervals (CI) were estimated from the model. Likelihood— based Chi—square tests (two—sided, 0: = 0.05) were used to test for n—group differences.

The analysis for secondary y variables was prespeci?ed for the 16 week time point for analysis of FEV1 and for overall effect at 16 weeks for lung function, patient-reported asthma outcomes, SABA use, blood eosinophil counts, time to ?rst CAE and CAE requiring use of systemic corticosteroids. Type I error was only controlled for at these ned secondary time points. An is of covariance model was used to compare least—squares mean changes from baseline to end-of-treatment endpoint for the above outcomes. A strati?ed Cochran-Mantel- Haenszel test was used to analyze the proportion of patients achieving a 2 0.5-point improvement from ne in AQLQ total score and a 2 0.5—point reduction in ACQ score.

These changes represent minimal clinically important differences. Pooled data was used to perform sub—group analyses (Table 19) for CAE and FEV1 analysis.

Baseline Demographics and baseline disease state characteristics in the randomizedpatient population Overall, 489 ts were randomized to reslizumab (n=245) or o (n=244) in Study 2, and 464 were randomized to reslizumab ) or placebo (n=232) in Study 3 (intention-to-treat populations). All except one patient in the placebo arm in Study 2 received ed study treatment; this patient was excluded from the safety analyses.

The baseline demographics and baseline disease state characteristics in the randomized patient populations for studies 2 and 3 are summarized in Table 14 below.

In each trial, baseline demographic characteristics were well balanced between the reslizumab and o arms. Baseline characteristics were also lly well balanced across the studies, except for numerical ences in race, oral corticosteroid use, and FEVl. _ 38 _ Baseline eosinophil counts were similar in both trials (660 and 649 cells/111 for Study 2 and 3 respectively). In Study 2, 85% of all randomized patients (placebo 84%, umab 85%) received all 13 doses of study medication; in Study 3, 83% of patients (placebo 83%, reslizumab 82%) received all planned doses. The majority of patients in both trials were receiving a LABA (86% Study 2; 82% Study 3).

Table 14 Median a_e ran_e — r 49 12—75 48 12—76 48 12—73 48 12—74 Male—no. % 83 34 103 42 82 35 88 38 White 182 75 173 71 169 73 168 72 Black 20 (8) 14 (6) 4 (2) 6 (3) Asian 33 14 50 20 21 9 16 7 42 18 Body mass index — kilogram 28.0 i 6.2 27.0 5.3 er suare meter Time since diagnosis — yr 18.8 i 14.2 19.7 i 15.2 18.7 i 13.3 18.2 :: 14.4 All (mean) ICS use at enrollment 847.7i 442.13 824.1i 380.28 756.9: 274.23 856.0: 588.40 — micrograms T Oral corticosteroid use Use at enrollment 46 (19) 46 (19) 27 (12) 27 (12) — no. % LABA use at enrollment 207 (85) 214 (87) 192 (83) 190 (82) — no. % Prebronchodilation — liters 1.93 i 0.80 1.89 i 0.73 2.00 i 0.67 2.13 :: 0.78 Percent predicted value 65.0 i 19.8 63.6 i 18.6 68.0 i 18.9 70.4 :: 21.0 prebronchodilation Reversibilit — % 26.3 i 18.1 26.1 i 15.5 28.7 i 23.8 28.1 :: 16.1 3.19 i 1.05 4.35 i 1.02 2.57 i 0.89 0.66 i 0.20 182 78 Puffs er da 2.7 i 3.2 2.9 a: 2.8 Mean blood eosinophil count, 624 d: 590 610 i 412 SD — cells er microliter CAEs in past 12 months — 2.1 d: 2.3 1.9 :1: 1.6 no./atient *Plus—minus values are given as means i standard deviation. casone propionate or lent at screening visit. :Prednisone equivalent at screening visit. §Asthma y of Life Questionnaire total and domain scores range from 1 to 7, with higher scores indicating better quality of life; a change of 0.5 points represents the minimal clinically ant difference.

?The Asthma Control Questionnaire score ranges from 0 to 6, with higher scores indicating worse control; a change of 0.5 points represents the minimal ally important difference (Id) **The Asthma m y Index summary score ranges from 0 to 1, with lower scores indicating worse symptoms; a change of 0.09 points ents the minimal clinically important difference. TTCAEs were de?ned as worsening of asthma requiring use of systemic corticosteroids (if not y receiving treatment) or a two—fold se in the dose of inhaled or systemic corticosteroids for 2 3 days, and/or the need for asthma—related emergency treatment (emergency room Visit, hospitalization, or duled physician’s of?ce Visit for zer or other urgent treatment).

Efficacy Reslizumab was associated with 50% (Study 2, CAE rate ratio of 0.90 versus 1.80; CI 0.37—0.67) and 59% (Study 3, 0.86 versus 2.11; CI 0.28—0.59) reductions in the adjudicated clinical asthma exacerbation rate compared with placebo over 52 weeks (both P<0.0001; primary endpoints) (Table 15). Reduction in CAEs de?ned by use of systemic corticosteroid for Z 3 days (the majority subgroup in both studies) was consistent with the primary ef?cacy result (Study 2, 55% reduction [0.72 (CI .99) versus 1.60 (CI 1.20— 2.15)]; Study 3, 61% reduction [0.65 (CI 0.40—1.05) versus 1.66 (CI 100—274)]. No signi?cant differences were observed between arms in terms of patients requiring hospitalization or emergency department treatment.

Time to first exacerbation was signi?cantly longer following reslizumab treatment compared with o (). The probability of not experiencing an exacerbation by week 52 was 44% (CI 38, 51) with placebo and 61% (CI 55, 67) with umab and 52% (CI 45.0, 58) and 73% (CI 66.8, 78.6), in Studies 2 and 3, respectively.

Pooled sub—analyses indicated that background (placebo) asthma exacerbation rates were ced by disease severity based on background medication (1.63, 1.84, and 2.04 events per patient per year for ICS, ICS plus a LABA, and OCS—dependent categories, respectively); patients receiving reslizumab achieved better exacerbation rate-ratios versus placebo regardless of the treatment they were receiving at baseline (C; Table 16).

In both trials, improvement in FEVI was evident for reslizumab versus placebo by the ?rst on-treatment assessment at Week 4 with meaningful improvements observed at 16 and 52 weeks (Table 15; ). The results of studies 2 and 3 con?rm the 16 week improvements in lung function seen for study 1. Furthermore, studies 2 and 3 demonstrate that lung function ements are sustained through week 52.

Reslizumab treatment also resulted in marked improvements versus placebo in AQLQ total score, ACQ score, and ASUI score (Table 15). Improvements were also seen as early as the ?rst on-treatment assessment (Week 4 for ACQ and ASUI; Week 16 for AQLQ) and _4()_ overall effect vs placebo was demonstrated over the 16 and 52—week ent periods (Table 15; ; ; ). The proportion of patients with a 20.5—point improvement from baseline to end-of—treatment in AQLQ total score was higher in the reslizumab arms versus the placebo arms (Study 2: 74% versus 65%, P=0.03; Study 3: 73% versus 62%, P=0.02). Similarly, the proportion of patients achieving a 20.5—point reduction from baseline to end-of—treatment in ACQ score was signi?cantly higher in the reslizumab arms (Study 2: 76% versus 63%, PS0.002; Study 3: 77% versus 61%, P<0.002). Change in SABA use was not signi?cantly different between arms (Table 15; ).

Reslizumab was associated with a ion in blood eosinophil counts compared with placebo (Table 15), which was nt by the ?rst on-treatment assessment at week 4 and sustained for the duration of the studies ().

Pooled sub—analyses trated a trend for increasing FEV1 improvement with increasing disease severity based on background medication, which was most evident at 52 weeks (0.081L, 0.113L and 0.151L for ICS, BA and OCS-dependent patients, respectively). (; Table 16).

Table 15 Num er 0 3 9 05 59 patients with at (54.1%) (37.6%) (45.3%) (25.4%) least 1 CAE — All episodes . . 0.50 (0.37, . . 0.41 (0.28, 0.67)*** 0.59)*** Episodes . . 0.45 (0.33, . . 0.39 (0.26, requiring ic 0.62)*** 0.5 8)*** corticosteroids for 2 3 da s Episodes . . 0.66 (0.32, . . 0.69 (0.29, requiring 1.36) 1.65) hospitalization or ER treatment Secondary A (95 A)0 Placebo Reslizumab o Reslizumab A (95% CI)§ endomts CI ~ Week 16 0.110 0.248 0.137 (0.08, 0.094 0.187 0.093 , 0.198 *** 0.155 ** 0.126 (0.06, 0.090 (0.003, 0.18 *** ** Week 52 0.79 .,0(014 023 (007 0.40,(— —0. 07)** 013)*** —0.26 (— . . -0.24 (—0.37, 0.39, — —0.11)*** 0.08 *** 006 ** 0..06(004, 0..,04(001 8 *** 0 6 ** 0.29) -0. 18 (-0. 50, Week 16 -118 -584 —466 (—514, —76 -555 -479 (-519, - -418)*** 439)*** Week 52 -127 -582 -455 (—491, -76 -565 -489 (-525, - -419)*** 453)*** *P S 0.05, **P S 0.01, ***P S 0.001.TTThe rate ratio represents the ratio of adjudicated CAE rates between the umab and o arms. IValues shown are least—squares mean changes over the speci?ed period from baseline, except for the week 16 AQLQ that represents the change to week 16. Week 16 was the ?rst time point where AQLQ was assessed. §The between—group difference is the absolute reduction in the reslizumab arm versus the placebo arm.

Table 16 ALL patients 476 1.8118 477 0.8359 0.4613 (0.37, 0.58) *** LABA YES 3 83 1. 84 397 0.83 0.45(0.35,0.58) LABA NO 1.63 0.84 051029 089 ocs deendent YES mm 032 0.18, 0.55 0.226 0.117 0.073,0.160 *** 0.224 0.110 0.066 0.154 *** 0.230 0.120 0.071, 0.169 0.227 0.113 0.063, 0.162 *P S 0.05, **P S 0.01, ***P 5 0.001. p—Value were only calculated only for the entire population: it was not calculated for subgroup analyses. T The rate ratio represents the ratio of adjudicated CAE rates between the reslizumab and placebo arms. iValues shown are least— square mean changes from ne. §The between—group difference is the absolute reduction in the reslizumab arm versus the placebo arm.

Table 17 0.137 0.126 0.072 0.145 (p <.0001) (p <.0001) (p = 0.0483) (p=0.0004) Study 3 0.093 0.090 0.101 0.123 (p=0.003 7) (p=0.0057) (p=0.0109) (p=0.0016) Study 1* 0.160 0.165 (p= 0.0018) (p= 0.018) Overall change takes into consideration all time points up to 16 or 52 weeks In?uence ofdisease severity (based on background controller medication) on reslizumab efficacy As illustrated in A and 21B, ts who commenced reslizumab treatment with a high dosage of inhaled osteroids (those ts requiring a higher steroid dosage to maintain control before treatment with reslizumab) bene?tted more from reslizumab treatment than those who were on a medium dosage of inhaled corticosteroids. "ICS," "ICS medium," and "ICS high" as used in A and 21B asses all six of the ICSs in Table 18. The de?nition of medium and high ICS dose are provided in Table 18.

Table 18. ICS cutoffs for subgroup analysis Total Dail dose mc_ ‘ Highe dium ICS (GEE/2351313) (ATS/ERS severe asthma guidance) asonea S 500 > 500 2 1000 Mometasoneb : 440 > 440 > 800 Budesonidec S 800 > 800 2 1600 Ciclesonide S 320 Beclomethasoned S 400 s 2000 >2000 22000 ICS (inhaled corticosteroid); S (American Thoracic Society/European Respiratory Society); GINA/NAEPP l Initiative on / National Asthma Education and Prevention Program) aAlthough ?uticasone HFA MDI has a cutoff of 440mcg and ?uticasone DPI has a cutoff of 500mcg, we ed the higher cutoff of 500mcg to prevent medium doses from being counted in the high group. bMometasone had cutoffs of 400mcg in NAEPP and 440mcg in GINA. Asmanex dosed as 110mcg or 220mcg, so the 440mcg cutoff makes more sense. cBudesonide, of note: Symbicort low dose is 80mcg 2 puffs BID = 320mcg and high dose is 160mcg 2 puffs BID = 640mcg, but 800 is the cutoff in both GINA and NAEPP so left it in the table. methasone CFC appears to have been discontinued. Beclomethasone HFA was 480mcg in NAEPP and 400mcg in GINA. Easyhaler and Clenil are usually 200mcg per dose and Qvar high starting dose is 160mcg BID, so a cutoff of 400mcg seems reasonable. 6The latest table from International ERS/ATS guidelines on de?nition, evaluation and treatment of severe asthma 2014 (Chung, K.F., et al. "International ERS/ATS guidelines on de?nition, tion and treatment of severe asthma." Eur Respir J (2014) 43 :343—373; table 4 — re roduced below ec omet asone 1proplonate or or _ ( _ ( 2320 (HFA MDI) 21000 (HFA MDI) Budesonide 2800 (MDI or DPI) 21600 (MDI or DPI) Ciclesonide 2160 (HFA MDI) 2320 (HFA MDI) Mometasone furoate 2500 (DPI) 2800 (DPI) Triamcinolone acetonide 21200 22000 Notes: 1) Designation of high doses is provided from manufacturers’ recommendations where possible. 2) As chloro?uorocarbon (CFC) preparations are being taken from the market, medication inserts for hydro?uoroalkane (HFA) preparations should be carefully reviewed by the ian for the equivalent correct dosage. DPI: dry powder r; MDI: metered-dose inhaler Safety Pro?le The most commonly reported adverse events (> 5%) in either study were asthma, aryngitis, upper respiratory tract infections, sinusitis, in?uenza and he. Of note, asthma worsenings were of special interest and were reported as adverse events, per protocol. The ncy of serious adverse events for placebo versus reslizumab in Studies 2 and 3 were 14% versus 10% and 10% versus 8%, tively. The most common serious adverse event was ing of asthma. Discontinuation e event frequency for Studies 2 and 3 for placebo versus reslizumab were 3% and 2% and 4% versus 3%, respectively. Infections were equally balanced between patients receiving o or reslizumab and no helminthic infestations were reported.

Two patients in the reslizumab arm in Study 3 experienced anaphylactic reactions that responded to standard therapy at the study site. There were no serious infusion reactions. Malignant neoplasms were uncommon in placebo (Study 2: colon cancer (n=1) and bladder cancer (n=l); Study 3: none) and in reslizumab groups (Study 2: lung cancer (n=2) and prostate cancer (n=l); Study 3: plasmacytoma . One placebo-treated patient in Study 2 died from multiple-drug intoxication.

Table 19 Placebo Reslizumab Placebo Reslizumab AE _ no. (%) (n = 243) (n = 245) (n = 232) (n = 232) All-grade AEs 206 (85) 197 (80) 201 (87) 177 (76) Upper respiratory tract 32 (13) infection Nasopharyngitis 33 (14) 28 (1 1) 56 (24) 45 (19) Sinusitis 29 (12) 21 (9) 10 (4) 9 (4) Nausea 10(4) 3 (l) 2 (<1) Bronchitis 24 (10) 13 (5) l4 (6) 2 (<1) Placebo Reslizumab Placebo Reslizumab (n = 243) (n = 245) (n = 232) (n = 232) AE _ no. (%) Urinary tract infection 11 (5) 13 (5) Allergic rhinitis 6 (2) 13 (5) Oropharyngeal pain 8 (3) -l3 (5) 3 (1) 5 (2) Back pain 13 (5) -l3 (5) 8 (3) 12 (5) Pharyngitis 13 (5) -10 (4) 8 (3) 7 (3) Cough 13 (5) 11 (4) Dyspnea 12 (5) 10 (4) Respiratory tract infection 5 (2) 6 (2) Dizziness 13 (5) 5 (2) Asthma 13 (5) ll (4) nia 0 2 (<1) Road traffic accident 0 0 AEs leading to 8 (3) 4 (2) discontinuation Deaths 1 (<1) 0 0 0 *The safety set included all ized patients who ed at least one dose of any study drug. AEs which occurred in 2 5% of patients in any arm during the study treatment period are listed, as are serious AEs which occurred in 2 1% of patients in any arm. Incidence is based on the number of patients experiencing at least one AE.

ABS of l interest are summarized below. - ensitivity/anaphylaxis remains a known risk: incidence < 1%. In study 3, 2 events reported as serious and resulting in d/c.

- Malignancy: In study 2, l prostate and 2 lung cancer were observed. The short latency tends to go against relatedness. In study 3, 1 case of plasmacytoma was observed.

- Infection: No Speci?c concern, no helminthic infestations reported.

- Administration site AE: similar to placebo.

- Infusion reactions: no serious events apparent. Investigator CRF re infusion relatedness — pending.

Immunogenicz'ly The incidence of a positive anti—drug antibody response in the reslizumab treatment groups for Study 2 and Study 3 was 2% and 5% at baseline (prior to reslizumab administration), with 2 1 positive response during the treatment period observed in 3% and 7%, tively. The majority positive ADA responses were low titer and transient (most being single observations that resolved). The safety pro?le of anti-drug antibodies (ADA) positive patients was not different from that observed in the overall population.

Conclusions These twin studies consistently demonstrated that umab signi?cantly improved outcomes in patients with inadequately controlled asthma and blood eosinophils 2400/ul. These results were achieved despite the continued use of prior therapies throughout. In the primary analysis reslizumab signi?cantly reduced the annual rate of clinical asthma exacerbations by 50—59% compared with placebo. Time to ?rst clinical asthma bation was also increased with reslizumab versus placebo.

Both study 2 and 3 met both the y and key secondary end points of reduction in the annual rate of CAE and improvement in lung function (FEV1). The safety pro?le of reslizumab supports a favorable -risk pro?le in patients with moderate to severe eosinophilic asthma whose symptoms are inadequately controlled with an ICS :: r controller.

Common AEs consistent with those expected in a moderate to severe asthma population and generally similar to placebo. Severe and tinuation AEs overall similar pro?le to o. Laboratory, ECG, vital signs and physical exam overall r to placebo in study 1 (these data are pending for studies 2 and 3). AEs of special interest include: hypersensitivity/anaphylaxis remains a known risk - incidence < 1%; malignant neoplasms for the program slightly more common on reslizumab than placebo se origin/commonly ing; not statistically different from all cancers in the Surveillance, Epidemiology, and End Result (SEER) data base June 2014); infection pro?le r to placebo, no speci?c concerns; administration site/infusion reactions pro?le similar to placebo in study 1 (full analysis of 2 and 3 data is pending).

Exam le 3: Stud 4 — characterize the ef?cac of reslizumab 3.0 m k on asthma control measures in on to baseline blood eosinophils The objective of study 4 was to characterize the ef?cacy of umab (3.0 mg/kg monthly) on asthma control measures in relation to baseline blood eosinophils in subjects with moderate to severe asthma. The primary endpoint was the change in FEV1 from baseline to Week 16. Secondary endpoints included: ACQ—7, Rescue inhaler (SABA) use, PVC, and safety measures. ion/exclusion criteria The study was performed on adults aged 18 to 65 years with uncontrolled moderate to severe asthma (ACQ score 21.5; at least ICS (2440 pg ?uticasone or equivalent) i another controller (e. g. LABA); and airway reversibility (212% to beta-agonist)). There was no ement for elevated blood EOS levels. There was no specific FEV1 or asthma exacerbation exclusion.

Study design and baseline demographics Study was a phase 3, double—blind, 16—week, randomized, placebo—controlled study in which patients were d with reslizumab 3.0 mg/kg or placebo every 4 weeks for 16 weeks. The baseline demographics of the patients are shown in Table 20. Baseline asthma characteristics are shown in Table 21.

Table 20 Age, mean, y 45.1 44.9 44.9 Male, % 45 34 36 66 64 6s 67 28 27 Asian 2 Ethnicity, % Non-Hispanic, non- Latino Bahama/1,12 Table 21 bation within 41 previous 12 months ACQ score, mean Airway reversibility, FEV1, mean, L FEV1,% predicted Rescue medication inhalations/previous 3 Blood EOS, mean 0.3 (0—1.3) 0.3 (0—1.6) 0.3 (0—1.6) (range), x109 cells/L d with LABA, 82 77 78 ACQ=Asthma Control Questionnaire; EOS, eosinophil; FEV1=forced expiratory volume in 1 second; ong-acting gonist.

Results The results of study 4 are summarized in Table 22 and . The primary ef?cacy analysis (linear regression) failed to show a signi?cant interaction between baseline blood eosinophil count and change in FEV1 at week 16 (p=0.2407; B). Overall change in FEV1 and categorical analyses based on different blood eosinophil cut-offs were prespeci?ed. ing 16 weeks of therapy, small, non-signi?cant improvements in asthma control were observed in the overall population. Patients with baseline eosinophils <400/11L, as a group, showed small improvements after the addition of reslizumab that would not be considered clinically meaningful. In contrast, large ent effects were generally observed in patients with blood eosinophil counts 2 400/11L; the low numbers of patients in the placebo arm that met this ion limit interpretation (Table 22 and ).

Table 22 Efficacy le o 3 mg/kg Placebo 3 mg/kg Placebo 3 mg/kg Randomized N=97 N=395 Patients FEV1 ( L) Baseline Mean 2.172 (0.0643) 2.098(00350) 2.182 (0.0746) 2.068 (0.0372) 2.153 (0.1392) 2.224 (0.0928) (SE) (0620—3800) (0470—4940) (0620—3800) (0470—4940) (1060—3550) (0660-4130) Range 0.175(00377) 0.251(00200) 0.215(00484) 0.247(00255) 0.002(01216)0.272(00557) LS Mean Change from Baseline (SE) Treatment Effect 0.076 (0.0417) 0.033 (0.0539) 0.270 (0.1320) Change (SE) 6, 0.158 (0.0697] [—0.073, 0.139 (05422)] [0.008, 0.532 (00436)] 95% CI, P-Value FVC ( L) Baseline Mean 3.209(00924) 3.041 (0.0481) 3.217(0.1095) 2.973 (0.0513) 3.206(01757) 3.321 (0.1234) (SE) (1320—6170) (0560—5920) (1320—6170) (0560—5770) -4.780)(1.250-5.920) Range 0.190 (0.0438) 0.253 (0.0232) 0.256(00537) 0.248 (0.0283) 0.055 (0.1449) 0.230 (0.0681) LS Mean Change from Baseline (SE) ent Effect 0.064 (0.0438) -0009 (0.0598) 0.175 (0.1571) Change (SE) [—0.03 1, 0.159 (01895)] [-0.126, 0.109 (08853)] 7, 0.487 (0.2675] 95% CI, P-Value ACQ (n=76) (n=77) Baseline Mean 2.574 (0.0698) 2.559(00353) 2.564(0.0778) 2.574 (0.0390) 2.677 (0.1692) 2.501 (0.0839) (SE) (1286—4857) (1286—5286) 4857) (1286—5286) (1.571 -4.143)(1.571 -4143) Range -0.614 (0.0689) -0737 (0.0364) -0714 (0.0954) -0.858 LS Mean Change (0.1105) from Baseline (SE) Treatment Effect -0123 (0.0762) -0122 (0.1065) —0.490 (0.2616) Change (SE) , 0.027 (01072)] [—0.332, 0.087 (02511)] [—1.010, 0.030 (00643)] 95% CI, P-Value SABA Use (n=96) (n=3 92) (n=76) (n=315) (n=18) (n=76) (puffs/day) Baseline Mean 2.0 (0.19) 1.9 (0.09) 2.0 (0.21) 1.9 (0.10) 2.2 (0.44) 1.9 (0.21) (0.0 — 8.7) (0.0 — 8.0) m0—8m @0—8m 0.0 — 6.7 0.0 — 8‘0 Range -02 (0.15) -03 (0.08) _0.4 (0.21) _0.2 (0.11) -0.1 (0.43) 0-.8 (0.19) LS Mean Change from Baseline (SE) Treatment Effect -0054 (0.1661) 0.216 (0.2300) -0.708 (0.4587) Change (SE) 0, 0.273 (07468)] [—0.236, 0.668 (0.3484] 9,0.204,(0.1264)] 95% CI, P-Value Adverse events The adverse events are summarized in Table 23. Serious ABS, with reslizumab treatment: 16 events (4%) spanning multiple SOC without apparent pattern. Of interest: laxis (X 2) (1 related (below); 1 therapy); and colon cancer (not related).

Discontinuation due to AEs: spanned multiple SOC without apparent pattern.

Table 23 21 AE, ANY 72 (74) 218 (55) 21 treatment-related AB 16 (16) 28 (7) 21 serious AB 4 (4) l6 (4) 21 discontinuation due to AB 12 (12) 29 (7) The most frequent AE by preferred term frequency 2 2% for umab are shown in Table 24.

Table 24 ast ma ( ) ( ) sinusitis 7 (7) 22 (6) nasopharyngitis 5 (5) headache 4 (4) cough 1 (1) 6 (2) Conclusion ction between treatment and baseline blood EOS count was not signi?cant based on simple linear regression. Treatment effects of reslizumab were small in the overall population (unselected for baseline EOS). Treatment effects were small in patients with baseline EOS S 400/uL as a group. The largest improvements in lung function and asthma control occurred in subjects with baseline EOS 2400/pL (the small number of subjects (n=13 at week 16) with EOS 2400/uL in the placebo group limits interpretation; 30% withdrawal in placebo group with baseline EOS 2400/uL and 10% for reslizumab group with ne 2400/uL). Four monthly doses of umab were well tolerated in subjects with moderate to severe asthma.

Example 4. Comparison of reslizumab and mepolizumab A comparison of reslizumab and mepolizumab inclusion and design are ized in Table 25.

Table 25 Asthma patients age 12 -75 Asthma patients 2 age 12 Physiology Physiology ° Reversible to SABA (12%) during ° Reversible to SABA, AHR, PEF or screening FEV1 variability ° No FEV1 upper limit Evidence of persistent air?ow obstruction (FEV1 % ted < 80% for age 18 or older, <90 % for age 12 to 17 or FEVl/FVC ratio < Blood eosinophil level 2 400/uL EOS 2 300 in prior 12 months or 150 at At least medium doses of ICS (2 440 pg of High dose ICS + another controller ?uticasone or equivalent) i another controller 2 1 asthma exacerbation previous 12 months 2 2 exacerbations previous 12 months uately controlled (ACQ 2 1.5) No apparent inclusion for t control OCS dependent asthma allowed OCS dependent asthma allowed IV dosing is weight based 3 mg/kg Fixed dose iv 75 mg or so 100 mg ° minimum weight of 45 kilogram reslizumab 3.0 mg/kg iv or placebo every 4 mepolizumab 75 mg iv, 100 mg sc or weeks x 13 doses PBO every 4 weeks x 8 ° EOT 52 weeks Doses ° EOT 32 weeks A comparison of primary ef?cacy CAE de?nitions in reslizumab and mepolizumab studies are summarized in Table 26.

Table 26 rease n the Use of system co oster01 use of inhaled, osteroid and/or and/or a hospitalization or ER visit 2. asthma-related emergency treatment including at least 1 of the following: ° an unscheduled visit to the physician’s of?ce for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms a visit to the emergency room for asthma related treatment an asthma-related hos n ation se in FEV1 by 20% or more E—Diary based from baseline decreased peak ?ow decrease in the peak tory ?ow increase in rescue medication rate (PEFR) by 30% or more from increased frequency of nocturnal baseline on 2 consecutive days awakening due to asthma worsening of symptoms or other T asthma symptoms clinical signs per physician evaluation of the event Bold font - Inde u l ad'udicated A comparison of primary and key secondary ef?cacy in reslizumab and mepolizumab s are summarized in Table 27.

Table 27 Study 3082 Reslizumab 3 mg/kg Study 3083 60% 61% 101 Reslizumab 3 p <.0001 p <.0001 p=0.0109 111.: Study 115588 MEPO 100 mg sc MEPO 75 mg iv DREAM MEPO 75 mg iV Study 3081 umab 3 m I I * MEPO slent on overall FEV improvements: ‘at’ time point contrasted above.

MEPO 100 mg sc (Study 115588) and 75 mg (DREAM) appear to reduce CAE requiring hospitalization and ER Visits. Reslizumab hospital and ER subanalyses pending.

Summary A robust improvement in FEV1 as early as week 4 that was maintained to week 16 was observed with reslizumab ent in asthma patients with elevated Eosinophils >400/pl (Eosinophilic asthma) already treated with ICS/LABA or ICS it another controller (e.g. LTRA).

Reslizumab also uniquely improved FEF25%75% and, in particular, Forced Vital Capacity (FVC), consistent with improvements in small airways obstruction (FEF25%_75%) and decreased hyperin?ation (overall FVC improvement) perhaps due to improvements in remodeling that was most prominent with the 3 mg/kg dose. Furthermore, s 2 and 3 indicated that the lung function bene?t, in terms of FEV1, was sustained through 52 weeks.

The differential effects in patients with >400 eosinophils vs <400 eosinophils seen in study 4 on a number of measures of lung function and asthma l suggest that these effects are unique to the t population of philic asthmatics. Measures of l (ACQ, rescue use) and lung function including PVC, and FEF25%_75% were ly impacted by reslizumab in asthma patients with elevated eosinophils >400/pl (eosinophilic asthma).

The results from study 1 demonstrated a signi?cant and meaningful effect on FEV1 as early as week 4 that was maintained to week 16 in asthma patients with elevated eosinophils >400/ul. This ?nding is remarkable in that it was seen in patients either on ICS/LABA (approx 80%) or ICS with or t controller(s) (e. g. LTRA — approximately 16% or LAMA approximately 4%). Additionally, the disclosed studies showed that reslizumab uniquely improves FEF25%_75% and, in particular, FVC, consistent with improvements in small airways obstruction (FEF25%_75%) and decreased hyperin?ation/improvement in remodeling (overall FVC improvement) that was most prominent with the 3 mg/kg dose.

Many clinical studies on other agents have demonstrated decreasing magnitude of se in more severe/compromised patients with no response in patients of this severity (e.g. LTRA). In contrast, as demonstrated in study 1, the improvements in FEV1 seen with 3 mg/kg IV reslizumab in patients with eosinophilic asthma on lung function were consistent even in ts with compromised lung function; this was con?rmed by the results seen with the 3 mg/kg dose in patients with baseline FEV1<85%.

As seen in study 1, reslizumab demonstrated meaningful ements from baseline in other control measures including the Asthma Control onnaire (ACQ) and quality of life (AQLQ) that represents a unique outcome in this severe patient population.

Example 5 — Treatment of patients having late—onset eosinophilic asthma Objectives Late—onset asthma with elevated blood eosinophils is a distinct and dif?cult-to- treat asthma ype. The objective of example 5 was to determine whether or not treatment with reslizumab reduces exacerbations and improves lung function in patients (pts) with late- onset asthma inadequately controlled on an inhaled corticosteroid (ICS)-based regimen and with elevated blood eosinophils.

Methods Data were pooled from two k placebo—controlled trials of reslizumab IV 3 mg/kg (every 4 weeks) in patients (12—75 years old) with uately controlled asthma (ACQ7 21.5 and 21 asthma exacerbation within 12 months) and screening blood phil counts 2400/uL. All events were ndently adjudicated. Annual rate of asthma exacerbations (de?ned as worsening events requiring onal corticosteroid and/or urgent asthma treatment) (A) and overall change in lung function (FEV1) (B) were strati?ed by age of asthma onset (<40 or 240 years old).

Overall, 476 and 477 patients were randomized to placebo and umab, respectively. 273 patients had late-onset asthma (age 240 years old at diagnosis); baseline characteristics for this group included mean age of 58.2 years old, 59% female, mean BMI: 27.9, ACQ6 score: 2.5, and FEV1: 1.84 L (67% predicted). Efficacy results by treatment and age of onset are displayed in .

Conclusion Reslizumab markedly reduced asthma exacerbations and improved lung function in patients with late-onset asthma and elevated blood phils. e 6 — In?uence of baseline eosinophil counts higher than 400/[51 Methods Post hoc analysis of pooled data from studies 3082 and 3083. CAE rate ratios and FEVl treatment effect (reslizumab—placebo) were stratified by singly exclusive eosinophil category ( > 400, > 500, > 600, > 700, > 800) Results As illustrated in A, no further effect of increasing baseline blood eosinophils beyond 400/[11 was observed on CAE. A modest increase in FEV1 improvement with increasing baseline blood eosinophils beyond 400ml (~30—50 ml) was observed, however, as illustrated in B.

Those d in the art will appreciate that us changes and modi?cations can be made to the preferred embodiments of the ion and that such changes and modi?cations can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

EMBODIMENTS The following list of ments is intended to complement, rather than displace or ede, the us descriptions.

Embodiment l. A method of treating moderate to severe eosinophilic asthma in a patient comprising: identifying a t having moderate to severe eosinophilic asthma, wherein the patient’s symptoms are inadequately controlled with a current asthma therapeutic and n the patient’s blood eosinophil levels are equal to or greater than 400/pl; and administering to said patient a therapeutically effective dose of reslizumab.

Embodiment 2. The method of embodiment 1, wherein the patient’s blood eosinophil levebzueequalu)orgrauerthanSOO/ul,600/u1,?00/u1,or800/u1.

Embodiment 3. The method of ment 1 or 2, wherein the therapeutically effective dose of reslizumab is about 0.3 mg/kg to about 3 mg/kg.

Embodiment 4. The method of embodiment 3, wherein the therapeutically effective dose of reslizumab is administered intravenously or subcutaneously.

Embodiment 5. The method of any one of the previous embodiments, wherein the therapeutically effective dose of reslizumab is administered once about every 4 weeks.

Embodiment 6. The method of any one of the previous embodiments, wherein the current asthma therapeutic comprises an inhaled corticosteroid.

Embodiment 7. The method of embodiment 6, wherein the current asthma therapeutic comprises a medium dose inhaled osteroid.

Embodiment 8. The method of embodiment 7, wherein the inhaled osteroid is at least equivalent to about 440 ug ?uticasone.

Embodiment 9. The method of embodiment 6, wherein the inhaled corticosteroid comprises a high dose of inhaled corticosteroid.

Embodiment 10. The method of any one of embodiments 6—9, n the current asthma therapeutic r comprises a long acting beta 2 adrenoceptor agonist. ment 11. The method of any one of the previous embodiments, wherein administration of the therapeutically effective dose of reslizumab leads to an improvement in lung function, as assessed by forced expiratory volume in 1 second, forced vital capacity, forced expiratory ?ow rate, or any combination thereof.

Embodiment 12. The method of ment 11, wherein the improvement in lung function is equal to or greater than about 5% as compared to a t not receiving reslizumab. ment 13. The method of any one of the previous embodiments, wherein administration of the therapeutically effective dose of umab leads to a reduction of clinical asthma exacerbations, reduction of use of systemic corticosteroids, improved asthma control questionnaire score, improved asthma quality of life questionnaire score, or any combination thereof.

Embodiment 14. The method of embodiment 13, wherein the clinical asthma exacerbations are d by about 50% as compared to a patient not receiving reslizumab.

Embodiment 15. The method of embodiment 13, wherein the use of systemic corticosteroids is reduced by about 50% as compared to a patient not receiving reshzunnab.

Embodiment 16. The method of any one of the previous embodiments, n the patient has late-onset asthma.

Embodiment 17. The method of embodiment 16, wherein administration of the therapeutically effective dose of reslizumab leads to a greater than about 90 ml change in forced expiratory volume in 1 second compared to a patient not ing reslizumab.

Embodiment 18. The method of embodiment 16 or 17, n administration of the therapeutically effective dose of reslizumab leads to an about 50% reduction in clinical asthma exacerbations ed to a patient not receiving reslizumab.

Claims (10)

1.WE CLAIM: 1. Use of reslizumab in the ation of a medicament for the ent of eosinophilic asthma in a patient, wherein: the patient had at least one asthma exacerbation requiring oral, intramuscular, or intravenous corticosteroid use in the previous 12 months, the patient's symptoms are inadequately controlled with an asthma therapeutic comprising an d corticosteroid, wherein the d corticosteroid comprises > 500 µg Fluticasone, > 440 µg Mometasone, > 800 µg Budesonide, > 320 µg Ciclesonide, > 400 µg Beclomethasone, or > 2000 µg Triamcinolone, and the patient's blood eosinophil levels are equal to or greater than 400/µ1.

2. The use of claim 1, wherein the patient's blood eosinophil levels are equal to or greater than 500/µ1, 600/µ1, 700/µ1, or 800/µ1.

3. The use of claim 1 or claim 2, wherein the dose of reslizumab in the medicament is about 0.3 mg/kg to about 3 mg/kg.

4. The use of any one of the previous claims, wherein the medicament is to be administered intravenously or subcutaneously.

5. The use of any one of the previous , wherein the medicament is to be stered once about every 4 weeks.

6. The use of claim 1, wherein the inhaled corticosteroid is at least equivalent to about 500 µg Fluticasone.

7. The use of claim 1, wherein the inhaled corticosteroid comprises = 1000 µg Fluticasone, > 800 µg Mometasone, = 1600 µg Budesonide, = 320 µg Ciclesonide, = 1000 µg Beclomethasone, or = 2000 µg Triamcinolone.

8. The use of any one of the previous claims, wherein the asthma eutic further comprises a long acting beta 2 adrenoceptor agonist.

9. The use of any one of the previous , wherein administration of the medicament leads to an improvement in lung function, as assessed by forced expiratory volume in 1 second (FEV1), forced vital capacity, forced tory flow rate, or any combination thereof. 10. The use of claim 9, wherein the improvement in lung function is equal to or greater than about 5% as compared to a patient not receiving reslizumab. 11. The use of any one of the previous claims, wherein administration of the ment leads to a reduction of clinical asthma bations, reduction of use of systemic corticosteroids, improved asthma control questionnaire score, improved asthma quality of life questionnaire score, or any combination thereof. 12. The use of claim 11, wherein the clinical asthma exacerbations are reduced by about 50% as compared to a patient not receiving reslizumab. 13. The use of claim 11, wherein the use of systemic corticosteroids is reduced by about 50% as compared to a t not receiving reslizumab. 14. The use of any one of the previous claims, wherein the patient has late-onset asthma. 15. The use of claim 14, wherein administration of the medicament leads to a greater than about 90 ml change in FEV1 compared to a patient not receiving reslizumab. 16. The use of claim 14 or claim 15, wherein administration of the medicament leads to an about 50% reduction in clinical asthma bations ed to a patient not receiving reslizumab. (L) «- Reslizumab 3.0 mg/kg FEVl —0 - Reslizumab 0.3 mg/kg Baseline 0.30 from 0.20 Change 0.10 Mean 0.00 Baseline Week 4 Week 8 Week 12 Week 16 Visit 9319. 1,21 0,4 A 160 ml, p=0.0018 0.35 A 115 m1, p=0.0237 (L) .0 t» FEVl 0.25 in .0N Change 0.15.0 I—d Placebo Resli 0.3 0. 126 0 4— umab 3.0 mg/kg FVC —0 ‘ Reslizumab 0.3 mg/kg in + Placebo 0.40 v Baseline 0.30 from 0.20 Change 0.

10.Mean 0.00 Baseline Week 4 Week 8 Week 12 Week 16 LS Visit Hg.