Original Article Efficacy and Safety of Reslizumab in Patients with Severe Asthma with Inadequate Response to Omalizumab: A Multicenter, Open-Label Pilot Study Luis A. Pérez de Llano, MD, PhDa, Borja G. Cosío, MD, PhDb,c, Christian Domingo, MD, PhDd,e, Isabel Urrutia, MD, PhDf, Irina Bobolea, MD, PhDc,g, Antonio Valero, MD, PhDc,g, Luis M. Entrenas Costa, MD, PhDh, Santiago Quirce, MD, PhDc,i, Pilar Barranco, MD, PhDc,i, Nuria Marina Malanda, MDj, Luis Prieto Andrés, MD, PhDk, and Francisco J. Alvarez-Gutiérrezl Lugo, Palma de Mallorca, Madrid, Sabadell, Barcelona, Bizkaia, Córdoba, Bilbao, Valencia, and Seville, Spain What is already known about this topic? Many patients with allergic eosinophilic asthma can qualify for different biologic therapies. In this clinical context, omalizumab is usually stated to be the first-line option, but there is a lack of information on the effectiveness of antieIL-5 mAbs if this drug fails to control asthma. What does this article add to our knowledge? This is the first prospective study to demonstrate the efficacy of using reslizumab in a patient population with severe allergic and eosinophilic asthma whose asthma was unresponsive to a biologic treatment targeting the IgE pathway. How does this study impact current management guidelines? This study can help clinicians to consider therapeutic alternatives in patients with severe asthma whose health-related quality of life is strongly affected. BACKGROUND: Patients with severe allergic and eosinophilic METHODS: We carried out a 24-week prospective, multicenter, asthma could qualify for different biologic therapies. open-label, single-group, self-controlled study in patients with OBJECTIVE: To evaluate the efficacy and safety of weight-based severe eosinophilic asthma who had previously failed to respond intravenous reslizumab dosing in patients who have previously to omalizumab. The main objective was to determine whether failed therapy with omalizumab. treatment with reslizumab significantly improved asthma a Pneumology Service, Hospital Universitario Lucus Agusti, Lugo, Spain Allergy, and Inmunotek. I. Urrutia reports personal fees from AstraZeneca, Chiesi, b Department of Respiratory Medicine, Hospital Universitario Son Espases-IdISBa, GlaxoSmithKline, Menarini, Mundipharma, Novartis, and Teva; and nonfinancial Palma de Mallorca, Spain support from Chiesi, GlaxoSmithKline, Mundipharma, Novartis, and Teva, outside the c CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, submitted work. I. Bobolea reports receiving fees as speaker or consultant for Novartis, Madrid, Spain GlaxoSmithKline, AstraZeneca, Teva, Chiesi, and Mundipharma, not related to the d Department of Pulmonary Medicine, Corporació Sanitària Parc Taulí, Sabadell, submitted work. A. Valero reports personal fees from AstraZeneca, Boehringer- Spain Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, and Sanofi, outside e Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain the submitted work. L. M. Entrenas Costa reports personal fees from AstraZeneca, f Asthma Unit, Department of Pulmonary Medicine, Hospital Galdakao, Bizkaia, Spain Boehringer-Ingelheim, Chiesi, Esteve, Ferrer, GlaxoSmithKline, Menarini, Mundi- g Allergy Section, Department of Pulmonology and Allergy, Hospital Clinic Barce- pharma, Novartis, Pfizer, and Teva; nonfinancial support from Chiesi, GlaxoSmithK- lona—Institute for Health Research (IdiBAPS), Madrid, Spain line, Mundipharma, Novartis, and Teva; and grants from Novartis, Roche, Sanofi, and h Pneumology Service, Hospital Universitario Reina Sofía, IMIBIC, Universidad de Teva, outside the submitted work. S. Quirce reports personal fees from Novartis, Córdoba, Córdoba, Spain AstraZeneca, GlaxoSmithKline, Teva, Boehringer-Ingelheim, Chiesi, Sanofi, and i Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Mundipharma; nonfinancial support from Novartis, AstraZeneca, GlaxoSmithKline, Madrid, Spain Teva, Sanofi, Boehringer-Ingelheim, Chiesi, and Mundipharma; and grants from j Department of Pulmonology, Hospital de Cruces, Bilbao, Spain Sanofi, outside the submitted work. P. Barranco reports personal fees from Glax- k Allergy Section, Hospital Universitario Dr Peset, Valencia, Spain oSmithKline, AstraZeneca, Chiesi, Teva, and Novartis, outside the submitted work. N. l Asthma Unit, Hospital Universitario Virgen del Rocío, Seville, Spain M. Malanda reports fees as speaker for Novartis, GlaxoSmithKline, Teva, Chiesi, and This study was endorsed by the Asthma Research Program of the Spanish Respi- Menarini, not related to the submitted work. L. P. Andrés reports no relevant conflicts of ratory Society (PII de Asma de SEPAR) supported by a grant from Teva Phar- interest. F. J. Alvarez-Gutiérrez has received travel support, speaker fees, or grants from maceutical Industries. ALK-Abelló, AstraZeneca, Bial, Boheringer-Ingelheim, Chiesi, Esteve, Glax- Conflicts of interest: L. A. Perez de Llano reports personal fees from Novartis, AstraZe- oSmithKline, Menarini, Mundipharma, Novartis, and Teva. neca, GlaxoSmithKline, Teva, Boehringer-Ingelheim, Chiesi, Sanofi, Mundipharma, Received for publication October 23, 2018; revised manuscript received and and Esteve; nonfinancial support from Novartis, GlaxoSmithKline, Teva, Boehringer- accepted for publication January 4, 2019. Ingelheim, Menarini, Mundipharma, and Esteve; and grants from AstraZeneca, Teva, Available online January 21, 2019. and Chiesi, outside the submitted work. B. García-Cosío reports personal fees from Corresponding author: Luis A. Pérez de Llano, MD, PhD, Pneumology Service, Novartis, AstraZeneca, Teva, Boehringer-Ingelheim, Chiesi, Sanofi, and Mundi- Hospital Universitario Lucus Agusti, Calle Doctor Ulises Romero, No. 1, Lugo pharma; nonfinancial support from Novartis, Teva, Boehringer-Ingelheim, and 27003, Spain. E-mail: eremos26@hotmail.com. Menarini; and grants from AstraZeneca, GlaxoSmithKline, Teva, Boehringer-Ingel- 2213-2198 heim, and Chiesi, outside the submitted work. C. Domingo declares having received Ó 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy financial support for travel, speaker bureaus, or grants from Novartis, Sanofi, Glax- of Allergy, Asthma & Immunology. This is an open access article under the CC oSmithKline, Teva, Boehringer-Ingelheim, Esteve, Almirall, AstraZeneca, Chiesi, BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Menarini, Takeda, Pfizer, Ferrer, Stallergenes, Alk-Abelló, Allergy Therapeutics, Hall https://doi.org/10.1016/j.jaip.2019.01.017 2277 2278 PÉREZ DE LLANO ET AL J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2019 line option,5 but there is a lack of information on the effec- Abbreviations used tiveness of other biologic agents if this drug fails to control ACQ- Asthma Control Questionnaire asthma. To our knowledge, only 1 published study addressed this ACT- Asthma Control Test issue, and this post hoc analysis of subgroups of patients from 2 ATS- American Thoracic Society randomized controlled trials concluded that “in the atopic ERS- European Respiratory Society FENO- fraction of exhaled nitric oxide phenotype of patients with severe eosinophilic asthma and a prior ICS- inhaled corticosteroid history of omalizumab use, mepolizumab was effective in IQR- interquartile range reducing exacerbations and improving outcomes related to asthma control.”6 Reslizumab is a humanized mAb of IgG4 subtype against IL-5 that has been proven to significantly reduce exacerbations in patients with asthma inadequately controlled on at least a symptoms assessed by the Asthma Control Test (ACT) at medium-dose inhaled corticosteroid (ICS) and greater or equal to week 24. Secondary objectives were to evaluate symptoms at 400 eosinophils/mL in peripheral blood.7 The aim of this study weeks 4 and 12, change in FEV1 at week 24, and the inci- was to evaluate the efficacy and safety of reslizumab in patients dence of severe exacerbations over the study period. with severe asthma who are both allergic and eosinophilic and RESULTS: Twenty-nine patients (62.1% women, median age, have previously failed therapy with omalizumab. 50.8 years) were included in the study. The median ACT score significantly increased from 13.0 (interquartile range, 8.0-18.0) at baseline to 21.0 (interquartile range, 14.0-24.0) at 24 weeks METHODS (P [ .002). Only 2 of 29 patients developed at least 1 severe We carried out a 24-week prospective, multicenter, open-label, exacerbation during follow-up and none of them required hos- single-group, self-controlled study in 10 tertiary centers across pitalization. Overall, 15 of 25 patients (60%) were considered as Spain. The first patient was included in April 2017, and the last being controlled (ACT score of ‡20 and no exacerbations) at patient’s last visit was in March 2018. The main objective was to week 24. The percentage of patients who were receiving daily determine whether treatment with intravenous reslizumab signifi- systemic corticosteroids significantly decreased from 72.4% to cantly improved asthma symptoms assessed by the Asthma Control 52.0% (P [ .019). Adverse events were mostly moderate and Test (ACT) at week 24. Secondary objectives were to evaluate within the range of previously reported side effects with symptoms at weeks 4 and 12, change in FEV1 at week 24, and the reslizumab. incidence of severe exacerbations over the 24-week study period. CONCLUSION: Reslizumab is an effective and safe option for The final study protocol was approved by Galicia’s Ethics patients with severe eosinophilic asthma and a history of Committee (Cod 2017/117) and the local ethics committees of the omalizumab failure. Ó 2019 The Authors. Published by participating centers. The study was conducted in accordance with Elsevier Inc. on behalf of the American Academy of Allergy, the latest version of the Declaration of Helsinki. Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- Subjects nc-nd/4.0/). (J Allergy Clin Immunol Pract 2019;7:2277-83) Patients were included after written informed consent was obtained according to the study protocol. The inclusion criteria were Key words: Asthma; Asthma management; Severe asthma; as follows: (1) patients aged between 18 and 70 years; (2) who met Omalizumab; Reslizumab the European Respiratory Society/American Thoracic Society (ERS/ ATS) guidelines8 definition of severe refractory asthma; (3) with history of omalizumab failure due to lack of effectiveness (persisting INTRODUCTION severe exacerbations and/or uncontrolled symptoms in patients with Asthma is a heterogeneous chronic disease of the airways that a poor or moderate response in the global evaluation of treatment can be stratified across several phenotypes and endotypes.1 Most effectiveness scale9) after a minimum of 16 weeks of treatment and/ patients with asthma are well controlled by standard inhaled or adverse side effects leading to discontinuation of the drug; and (4) therapies, but approximately 4% of the total adult asthma pop- blood eosinophil count of 400/mL or more at least once in the 3-year ulation needs additional biologic therapies because of uncon- period before visit 1 or at this initial visit. Patients were excluded if trolled asthma and/or recurrent exacerbations, often requiring (1) they were diagnosed with asthma-chronic obstructive pulmonary prolonged courses of oral corticosteroids.2 Severe asthma has a disease overlap; (2) they had a smoking history of 10 or more pack- strong impact on the patient’s health-related quality of life and years; (3) they received the last dose of omalizumab within the health care resource utilization.3 It has been reported that nearly preceding 5 months from the date of visit 1; (4) there was previous half of this population shows an eosinophilic inflammatory exposure to another mAb; and (5) any other severe disease was likely pattern.4 Such patients can benefit from add-on biologic thera- to interfere with the conduct of the study. pies targeting IL-5, given the key role played by this cytokine in inducing, maintaining, and amplifying airway eosinophilia. Definitions Different biologic agents targeting IgE (omalizumab), IL-5, and Asthma: It is diagnosed—in accordance with the Spanish Asthma the IL-5 receptor (mepolizumab, reslizumab, and benralizumab) Guidelines10—by the presence of symptoms of wheeze, breathless- are currently available. It is difficult to choose the optimal ness, or cough plus a positive bronchodilator test result (significant treatment for a patient—with allergic and eosinophilic asthma— improvement by >12% and 200 mL in the FEV1 10 minutes after who could qualify for different biologic therapies. In this clinical the inhalation of 200 mg of salbutamol) or a positive methacholine scenario, some authors support the use of omalizumab as a first- challenge test result (a provocative concentration of methacholine of J ALLERGY CLIN IMMUNOL PRACT PÉREZ DE LLANO ET AL 2279 VOLUME 7, NUMBER 7 <4 mg/mL required to decrease the FEV1 by 20%) or high frac- Management and treatment of asthma exacerbations were left to tional exhaled nitric oxide (FENO) levels (>50 ppb). the criteria of the investigators, on the basis of current standard Severe asthma: According to the international ERS/ATS guide- of care.10 lines, this is defined as asthma that requires treatment with high-dose ICSs plus a second controller and/or systemic corticosteroids to Statistical methods prevent it from becoming “uncontrolled” or that remains uncon- The sample size was calculated on the basis of the assumption that trolled despite this therapy.8 a 3-point increase in ACT score from baseline to the final visit is a Controlled asthma: This is defined as asthma with a composite of clinically meaningful difference.16 A sample size of 24 patients ACT score of more than 19, and the absence of exacerbations during would provide a power of 80% with an a error of 0.05. Taking into the 24-week treatment period. account a possible loss to follow-up of 25% and considering previous Severe asthma exacerbation: It is an event characterized by a studies,17 it was decided to enroll 30 patients. clinically judged worsening of asthma control as evidenced by We performed the statistical analysis of the primary and sec- worsening symptoms and that resulted in use of systemic cortico- ondary end points in the intention-to-treat population, which steroids and/or hospitalization.11 included all patients who received at least 1 dose of the study drug, irrespective of possible protocol violations (eg, lost to follow-up or discontinuation of study drug). Study protocol Continuous variables were described by medians and interquartile At the initial visit (visit 1), patients were started on reslizumab ranges (IQRs), and categorical variables were described by using the 3 mg/kg intravenously every 4 weeks and followed up at the relative and absolute frequencies. respective participating outpatient clinics at 4, 12, and 24 weeks To evaluate differences in asthma outcomes between visits, cat- during the study period. At visit 1, researchers obtained and recorded egorical variables were compared using c2 analysis. On the basis of in an electronic clinical research database anthropometric data, their distributions, continuous variables were compared between smoking history, atopic status assessed by skin prick testing, clinical visits with Wilcoxon matched-pairs signed rank test or Student t test. history and lung function data, presence of comorbidities, pharma- All analyses were performed using SPSS Statistics version 22 (IBM cologic treatments, exacerbations, and symptoms assessed by the Corporation, Armonk, NY). validated Spanish version of the ACT12 and by the Asthma Control Questionnaire (ACQ). Lung function, exacerbations during the previous year, ACT score, ACQ score, adverse events, and blood RESULTS samples to measure absolute and relative eosinophil counts were also Demographic characteristics collected at every follow-up visit. Twenty-nine patients were included in the study. Omalizu- Subjects were terminated from participation in the study if they mab had been discontinued in 23 patients (79.3%) because of met 1 or more of the following criteria: (1) violation of the study the lack of effectiveness and in 6 (20.7%) because of side effects protocol during the study period, (2) lost to follow-up during the (see Table E1 in this article’s Online Repository at www.jaci- study period, (3) consent withdrawal, and (4) intolerable side effects inpractice.org). Demographic and clinical characteristics at visit of reslizumab or any severe adverse event related to the study drug. 1 are presented in Table I. Briefly, 62% were female, the median age was 50 years, 89.6% had positive skin prick test results (this implies that omalizumab was indicated on a compassionate, off- Spirometry and bronchodilator test label basis in 3 nonatopic subjects), and 72% were on daily Spirometry was performed at every visit by using equipment and systemic corticosteroids. techniques that met standards developed by the Spanish Respiratory Figure 1 shows the flowchart of patients through the study. Society (SEPAR).13 We have used the reference values for pulmo- Three patients were lost to follow-up at any time during the nary function testing developed by the Barcelona Collaborative study and 1 was withdrawn from the study because of a serious Group.14 Spirometry results included pre-/postbronchodilator FEV1 adverse event (toxicoderma). (in liters) and % predicted value, forced vital capacity (in liters and percentage of predicted), and the ratio of FEV1 and forced vital Effect on asthma control capacity. Bronchodilator response was defined as an increase in For the primary end point at 24 weeks, the median ACT score postbronchodilator FEV1 of more than 12% and more than 0.2 L significantly increased from 13.0 (IQR, 8.0-18.0) to 21.0 (IQR, (measured 15 minutes after inhalation of 200 mg of salbutamol, 14.0-24.0) (P ¼ .002). The improvements from baseline were using a spacer) compared with prebronchodilator FEV1. also significant at 4 and 12 weeks: 21.0 (IQR, 13.0-24.0) and FENO was measured by a chemiluminescence analyzer (NIOX 21.0 (IQR, 15.0-24.0), respectively (P < .001) (Figure 2, A). Mino, Aerocrine, Stockholm, Sweden) at a flow rate of 50 mL/s, in Sixteen of 25 patients (64%) achieved the minimal clinically accordance with the recommendations of the ERS/ATS task force.15 meaningful difference (at least 3 points) at the 24-week timepoint. Treatment schedule The median 7-item ACQ score significantly improved from 2.4 Bronchodilators, ICSs, antileukotrienes, antihistamines, nasal (IQR, 1.7-3.6) at baseline to 1.4 (IQR, 0.9-2.7) at 4 weeks (P < corticosteroids, and comorbidity-related medication remained un- .001), 1.3 (IQR, 0.6-2.4) at 12 weeks (P < .001), and 1.9 (IQR, changed during the study period, whereas the dose of systemic 0.9-2.6) at 24 weeks (P ¼ .004) (Figure 2, B). Thirteen of 25 corticosteroids was allowed to be adjusted according to the in- patients (52%) achieved the minimal clinically meaningful dif- vestigator’s judgment. Reslizumab was administered as 3 mg/kg ference (at least 0.5 points). The median Asthma Quality of Life every 4 weeks by intravenous infusion over 20 to 50 minutes in a Questionnaire score significantly increased from 4.1 (IQR, 3.0- health care setting by a health care professional prepared to manage 5.1) at baseline to 5.9 (IQR, 4.2-6.3) at 4 weeks (P < .001), 6.0 anaphylaxis. (IQR, 4.5-6.5) at 12 weeks (P < .001), and 5.6 (IQR, 4.4-6.6) at 2280 PÉREZ DE LLANO ET AL J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2019 24 weeks (P < .001) (Figure 2, C). The minimal clinically sig- TABLE I. Characteristics of patients according to the treatment nificant difference of 0.5 points or more in the Asthma Quality of regimen (N ¼ 29) Life Questionnaire was observed in 16 of 25 patients (64%). Variable Value* Secondary end points: Exacerbations, systemic Age (y) 50.8 (42-64) corticosteroids, and lung function Sex, female 18 (62.1%) Only 2 of 29 patients developed at least 1 severe exacerbation Positive skin prick test results 26 (89.6%) requiring initiation of systemic corticosteroids during follow-up IgE (IU/mL) 105 (44.9-212) and none of them required hospitalization. Overall, 15 of 25 Chronic rhinosinusitis 22 (75.8%) patients (60%) were considered as being controlled (composite of Polyposis 12 (41.4%) ACT score of 20 and no exacerbations) at week 24. SAHS 2 (6.4%) Although the study did not include a corticosteroid-tapering ABPA 1.0 (3.4%) preestablished regimen, the percentage of patients who were GERD 7 (24.1%) receiving daily corticosteroids significantly decreased from 72.4% Obesity† 9 (31%) to 52.0% (P ¼ .019). Mean prednisone equivalent dose was 16 Anxietyz 10 (34.5%)  14.9 mg at baseline (18 patients) and 19.0  18.2 mg at week Depressionz 6 (20.7%) 24 (13 patients). ACT score 13.0 (8.0-18.0) The median FEV1 increased from 1.6 L (IQR, 1.3-2.3) at ACQ-7 score 2.4 (1.7-3.6) baseline to 1.9 L (IQR, 1.3-2.5) at 4 weeks (P ¼ .1) and 1.8 L AQLQ score 4.1 (3.0-5.1) (IQR, 1.2-2.7) at 24 weeks (P ¼ .1) (Figure 2, D). At the end of FEV1 (L) 1.6 (1.3-2.3) the treatment period, 12 patients improved to 0.1 L or more and FEV1 (% predicted) 54.4 (42-73) 8 patients to more than 0.2 L. The median total blood eosinophil Severe exacerbations in the previous 12 mo 1.0 (0.0-2.0) count decreased from 330 cells/mm3 (IQR, 200-500) at baseline 1 severe exacerbation in the previous 12 mo 17 (58.6) to 70 cells/mm3 (IQR, 20-100) at week 4 and to 70 cells/mm3 Annual exacerbation rate 1.8  1.0 (IQR, 0-100) at week 24. The median FENO value decreased Corticosteroid-dependent patients 21 (72.4%) from 43.0 ppb (IQR, 25.6-63.7) at baseline to 34.5 ppb (IQR, Eosinophils (cells/mm3) at baseline 330 (200-500) 23.3-59.6) at week 24. FENO (ppb) 43.0 (25.6-63.7) Safety ABPA, Allergic bronchopulmonary aspergillosis; ACQ-7, Asthma Control Ques- In this study, adverse events were mostly moderate and within tionnaire (7 items); AQLQ, Asthma Quality of Life Questionnaire; GERD, gastro- the range of previously reported side effects with reslizumab. The esophageal reflux; SAHS, sleep apnea-hypopnea syndrome. only severe adverse reaction to reslizumab during the study was 1 *Data are median (IQR) or n (%). case of toxicoderma (<12 hours after the administration of the †Obesity is defined as body mass index score of 30 kg/m2. zAnxiety and depression diagnoses were collected from the medical history. These fourth dose of the drug, the patient developed symmetrical rash were assessed by the Hospital Anxiety and Depression Scale. affecting predominantly her trunk and proximal limbs) that completely resolved after stopping reslizumab and treatment with almost half the population. In addition, although the study was antihistamines and systemic corticosteroids. We believe that this not designed to actively taper corticosteroids to the lowest adverse effect was caused by the administration of reslizumab, possible dose, a remarkable proportion of patients (20%) were because there was a clear time relation between the use of the able to discontinue this medication. It is quite possible that this drug and the occurrence of the reaction, and toxicoderma dis- rate might have been improved by applying a predetermined appeared after medical treatment and it did not relapse after strategy for reducing the dose of systemic steroids, but this re- reslizumab withdrawal. Another patient suffered a vertebral mains to be demonstrated. It is also worth mentioning that a fracture that was not deemed to be reslizumab-related. Erythema high percentage of the study participants (72%) were at the site of administration was observed in 2 patients. The corticosteroid-dependent. This is not so surprising when various adverse events are listed in Table E2 in this article’s considering that this treatment was the only therapeutic alter- Online Repository at www.jaci-inpractice.org. native for patients with severe uncontrolled asthma before the approval of biologic drugs other than omalizumab, but it should DISCUSSION not affect the generalizability of the results to a wider range of This proof-of-concept pilot study shows that reslizumab can patients because, to date, steroid dependence has not been be an effective alternative therapy for patients with severe established as a predictor of response to antieIL-5 drugs. eosinophilic asthma who had previously failed to respond to Very few previous studies have tried to demonstrate that omalizumab. It shows that reslizumab significantly improved patients with severe asthma who do not respond to omalizumab symptoms and quality of life as early as week 4 and the can be subsequently and effectively treated with antieIL-5 improvement was maintained throughout the 24 weeks of the therapy. A post hoc analysis of 2 clinical trials (Mepolizumab as study. The treatment has proven to be safe, and there was only 1 Adjunctive Therapy in Patients with Severe Asthma [MENSA] serious reslizumab-related adverse event (toxicoderma) leading to and Steroid Reduction with Mepolizumab Study [SIRIUS]),18,19 study medication withdrawal. Although the study was neither which aimed to evaluate the effect of mepolizumab in patients planned nor powered to detect a reduction in exacerbations, it with severe eosinophilic asthma who had previously been treated must be highlighted that only 2 patients developed at least 1 with omalizumab, found that the reductions in the rate of ex- severe exacerbation during the treatment period. Moreover, there acerbations and in oral corticosteroid dose were comparable was a clinically relevant improvement in FEV1 (0.1 L) in regardless of previous omalizumab use. In addition, the 5-item J ALLERGY CLIN IMMUNOL PRACT PÉREZ DE LLANO ET AL 2281 VOLUME 7, NUMBER 7 eosinophilia in some patients with severe prednisone- dependent asthma, but higher doses of another antieIL-5 mAb (intravenous reslizumab) can control the airway eosino- philic inflammation leading to an improvement in asthma control.22 Our study has a similar design (the patients were sequentially treated with 2 mAbs) but the drugs (omalizumab and reslizumab) belong to a different pharmacological class. Taken together, the 2 studies provide some evidence that asthma control can be gained either by switching between 2 different antieIL-5 mAbs (when given at different doses) or by switching between biologic drugs that target a related, but different, inflammatory pathway.23 This study also emphasizes the effectiveness and safety of intravenous reslizumab in patients with an allergic phenotype, which may have potential clinical implications when deciding the most appropriate biologic therapy for a given patient. In severe allergic and eosinophilic asthma, both IgE and eosino- phils are components of a complex inflammatory process in which they have different roles. It is generally accepted that IgE plays a fundamental role in the triggering, development, and chronicity of the inflammatory responses in allergic asthma, whereas eosinophils are final effector cells in this process. The quantitative importance of each mediator is probably different in each individual patient with asthma and the available bio- markers are not precise enough to assess these differences. In our population, most of the patients with asthma (89%) had a positive skin test result and the median eosinophil count at baseline was 330 cells/mm3. In this clinical scenario, the deci- sion on which drug is the best choice remains difficult and challenging for the clinicians. Because it is generally considered that IgE is the cause of allergic airway inflammation rather than FIGURE 1. Flowchart diagram of the study. the consequence of this process, omalizumab has been mainly advocated to treat patients with allergy, although some positive outcomes have also been observed in nonallergic ones.24,25 ACQ and St George’s Respiratory Questionnaire scores were However, antieIL-5 are molecules that target the eosinophils, reduced with mepolizumab treatment compared with placebo in effector cells located at the end stage of the adaptive and innate both omalizumab-experienced and omalizumab-naive patients, immunity. Apparently, according to the results of the literature, pointing toward an improvement in asthma control and quality patients with allergy with a high blood eosinophil count would of life in patients previously treated with omalizumab. In this qualify for both treatments. In this regard, in a post hoc analysis respect, these results are concordant with ours. of pooled results from 2 randomized controlled trials, benrali- Our study responds to a clinical need, because there are pa- zumab has been shown to be effective for patients with severe tients with severe asthma, considered as allergic, who have poor uncontrolled eosinophilic asthma regardless of serum IgE con- response to omalizumab. In the present study, omalizumab had centrations and atopy status.26 Nonetheless, no head-to-head previously been discontinued mostly because of the lack of effi- studies have been performed to elucidate this issue. Although cacy in the included patients, although the reason for discon- our study does not pretend to clarify this issue, it shows that at tinuation was “adverse events” in 20.7% of the sample. Previous least some of these patients, considered nonresponders to studies report similar figures. In randomized controlled trials, the omalizumab, will benefit from antieIL-5 mAbs. dropout rate (an index that considers withdrawal due to lack of Our study has some strengths and limitations. To our efficacy and adverse events) ranges from 7.1% to 19.4%. In real- knowledge, this is the first clinical trial specifically designed to life studies, the dropout rate ranges from 0% to 45.5%.20 In demonstrate that patients who fail to respond to antieIgE Spain, the Spanish Severe Asthma Registry found a dropout rate therapy can be rescued with an antieIL-5 drug. Because of of 18.7%: 10.5% due to lack of efficacy, 5.6% on patients’ own the lack of a control group, a placebo effect cannot be definitely initiative, and 2.6% due to side effects.17 The response to ruled out. Nonetheless, besides the treatment with reslizumab, omalizumab does not seem to be related to the baseline eosin- little else over the course of the study could have caused the ophil count, because a recent study shows that a large proportion observed improvement in the patients’ clinical condition. The of patients with severe allergic asthma have a blood eosinophil significant increase in ACT score occurred together with a count of greater than or equal to 300 cells/mL and concludes that marked improvement in quality of life, asthma control, and omalizumab effectiveness is similar in “high” and “low” eosino- pulmonary function, giving consistency to the overall results. phil subgroups.21 Moreover, the local ethics committee interpreted that the use of It has been shown that 100 mg subcutaneous mepolizumab a placebo arm could be considered unethical in patients who are every 4 weeks may not be effective in reducing airway mostly being treated with oral corticosteroids and might qualify 2282 PÉREZ DE LLANO ET AL J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2019 FIGURE 2. Changes in asthma outcomes over the study period. A, Changes in ACT score over the 24-week study period. B, Changes in 7-item ACQ (ACQ-7) score. C, Changes in AQLQ score. D, Changes in FEV1. AQLQ, Asthma Quality of Life Questionnaire. for an existing antieIL-5 mAb. Another limitation is the rela- targeting the IL-5 pathway in patients with severe eosinophilic tively small population studied, but the estimated sample size asthma with previous omalizumab failure. (24 patients) was reached (25 patients completed the study) and it was powered to show statistically significant differences from baseline. In addition, the duration of the trial was too short to explore the effects on exacerbations. However, fewer exacerba- Acknowledgments tions and a positive effect on lung function were observed in We thank APICES (Madrid, Spain) for its participation in the most patients. project management, monitoring, data management, and statis- tical analysis of this study. CONCLUSIONS REFERENCES This is the first prospective study to demonstrate the efficacy 1. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit of using an antieIL-5 drug in a patient population with severe Care Med 2015;192:660-8. 2. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. allergic and eosinophilic asthma whose asthma was unresponsive The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015;135: to a biologic treatment targeting the IgE pathway. Reslizumab 896-902. has been shown to be effective and safe in improving outcomes 3. Chipps BE, Zeiger RS, Borish L, Wenzel SE, Yegin A, Hayden ML, et al. Key related to asthma control (symptoms and quality of life) in pa- findings and clinical implications from The Epidemiology and Natural History tients with severe eosinophilic asthma and a history of omali- of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2012;130:332-42. zumab use. The results of our trial should be viewed as 4. Schleich F, Brusselle G, Louis R, Vandenplas O, Michils A, Pilette C, et al. hypothesis-generating and in need of testing with a long-term Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma randomized controlled trial to assess the clinical efficacy of Registry (BSAR). Respir Med 2014;108:1723-32. J ALLERGY CLIN IMMUNOL PRACT PÉREZ DE LLANO ET AL 2283 VOLUME 7, NUMBER 7 5. Bousquet J, Brusselle G, Buhl R, Busse WW, Cruz AA, Djukanovic R, et al. 16. Schatz M, Kosinski M, Yarlas A, Hanlon J, Watson ME, Jhingran P. The Care pathways for the selection of a biologic in severe asthma. Eur Respir J minimally important difference of the Asthma Control Test. J Allergy Clin 2017;50:1701782. Immunol 2009;124:719-23. 6. Magnan A, Bourdin A, Prazma CM, Albers FC, Price RG, Yancey SW, et al. 17. Vennera Mdel C, Pérez De Llano L, Bardagí S, Ausin P, Sanjuas C, Treatment response with mepolizumab in severe eosinophilic asthma patients González H, et al. Omalizumab therapy in severe asthma: experience from the with previous omalizumab treatment. Allergy 2016;71:1335-44. Spanish registry—some new approaches. J Asthma 2012;49:416-22. 7. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, 18. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. et al. Reslizumab for inadequately controlled asthma with elevated blood Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J eosinophil counts: results from two multicentre, parallel, double-blind, Med 2014;371:1198-207. randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015;3: 19. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. 355-66. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. 8. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. Inter- N Engl J Med 2014;371:1189-97. national ERS/ATS guidelines on definition, evaluation and treatment of severe 20. Caminati M, Senna G, Stefanizzi G, Bellamoli R, Longhi S, Chieco-Bianchi F, asthma. Eur Respir J 2014;43:343-73. et al, North East Omalizumab Network Study Group. Drop-out rate among 9. Lloyd A, Turk F, Leighton T, Canonica GW. Psychometric evaluation of Global patients treated with omalizumab for severe asthma: literature review and real- Evaluation of Treatment Effectiveness: a tool to assess patients with moderate- life experience. BMC Pulm Med 2016;16:128. to-severe allergic asthma. J Med Econ 2007;10:285-96. 21. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M, STELLAIR 10. Guía española para el manejo del asma (GEMA). Arch Bronconeumol 2015;51: Investigators. Omalizumab effectiveness in patients with severe allergic asthma 2-54. according to blood eosinophil count: the STELLAIR study. Eur Respir J 2018; 11. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, 51:1702523. et al. An official American Thoracic Society/European Respiratory Society 22. Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, statement: asthma control and exacerbations: standardizing endpoints for clin- et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate ical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180: response to fixed-dose subcutaneous mepolizumab. Am J Respir Crit Care Med 59-99. 2018;197:38-46. 12. Vega JM, Badia X, Badiola C, López-Viña A, Olaguíbel JM, Picado C, et al. 23. Domingo C. Overlapping effects of new monoclonal antibodies for severe Validation of the Spanish version of the Asthma Control Test (ACT). J Asthma asthma. Drugs 2017;77:1769-87. 2007;44:867-72. 24. Garcia G, Magnan A, Chiron R, Contin-Bordes C, Berger P, Taillé C, et al. 13. García-Río F, Calle M, Burgos F, Casan P, Del Campo F, Galdiz JB, et al. A proof-of-concept, randomized, controlled trial of omalizumab in patients with Espirometría. Normativas SEPAR. Arch Bronconeumol 2013;49:388-401. severe, difficult-to-control, nonatopic asthma. Chest 2013;144:411-9. 14. Roca J, Sanchis J, Agusti-Vidal A, Segarra F, Navajas D, Rodriguez-Roisin R, 25. de Llano LP, Vennera Mdel C, Álvarez FJ, Medina JF, Borderías L, Pellicer C, et al. Spirometric reference values from a Mediterranean population. Bull Eur et al. Effects of omalizumab in non-atopic asthma: results from a Spanish Physiopathol Respir 1986;22:217-24. multicenter registry. J Asthma 2013;50:296-301. 15. ATS/ERS recommendations for standardized procedures for the online and 26. Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy offline measurement of exhaled lower respiratory nitric oxide and nasal nitric by atopy status and serum immunoglobulin E for patients with severe, uncon- oxide, 2005. Am J Respir Crit Care Med 2005;171:912-30. trolled asthma. Ann Allergy Asthma Immunol 2018;120:504-511.e4. 2283.e1 PÉREZ DE LLANO ET AL J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2019 ONLINE REPOSITORY TABLE E1. Reasons for omalizumab discontinuation Reason for discontinuation Lack of efficacy Duration of omalizumab No. of severe Patient treatment (mo) exacerbations ACT GETE Adverse effects 1 6 1 17 Moderate Generalized arthromialgias 2 3 0 20 Good Generalized arthromialgias 3 11 4 18 Moderate 4 23 3 10 Poor 5 36 1 11 Moderate 6 23 8 12 Moderate 7 18 3 9 Poor 8 12 3 16 Moderate 9 6 2 17 Poor Generalized arthromialgias 10 9 6 16 Poor 11 12 4 12 Poor 12 3 1 17 Moderate Generalized arthromialgias 13 4 1 8 Poor 14 6 0 17 Moderate Generalized arthromialgias 15 6 0 15 Poor 16 24 1 9 Poor 17 32 3 12 Poor 18 9 2 8 Poor 19 36 10 12 Poor 20 8 2 20 Poor 21 12 6 5 Poor Generalized arthromialgias 22 24 0 17 Poor 23 11 3 13 Poor 24 40 1 12 Poor 25 9 0 18 Moderate Generalized arthromialgias 26 11 0 18 Poor 27 12 2 19 Moderate Generalized arthromialgias 28 9 3 12 Poor 29 15 3 16 Poor GETE, Global evaluation of treatment effectiveness. Note. GETE measures response to asthma treatment on a 5-point scale: excellent (complete control of asthma); good (marked improvement in asthma); moderate (discernible, but limited improvement in asthma); poor (no appreciable change in asthma); and worsening of asthma. J ALLERGY CLIN IMMUNOL PRACT PÉREZ DE LLANO ET AL 2283.e2 VOLUME 7, NUMBER 7 TABLE E2. Adverse events Intensity Cases of adverse Treatment-related Treatment Adverse event events adverse event Mild Moderate Severe discontinued Toxicoderma 1 1 0 0 1 1 Vertebral fracture 1 0 0 0 1 0 Nasopharyngitis 3 0 3 0 0 0 Tracheitis 1 0 1 0 0 0 Bronchitis 6 0 3 2 1 0 Influenza 4 0 4 0 0 0 Pseudomonas bronchitis 1 0 0 0 1 0 Erythema 2 2 1 1 0 0 Pruritus 2 2 2 0 0 0 Erectile dysfunction 1 0 1 0 0 0 Breast pain 1 0 1 0 0 0 Dizziness 1 0 1 0 0 0 Headache 3 0 2 0 1 0 Vertigo 1 0 1 0 0 0 Diarrhea 1 0 1 0 0 0 Nausea 1 0 1 0 0 0 Gastritis 1 0 1 0 0 0 Abdominal pain 2 0 2 0 0 0 Asthenia 4 4 2 2 0 0 Pyrexia 1 0 0 0 1 0 Arthromialgia 10 3 8 2 0 0 Arterial hypertension 3 0 3 0 0 0