asthma: integrating biologic therapies for improved

Asthma: Integrating Biologic Therapies for Improved Outcomes CME

Supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

www.medscape.org/viewarticle/920387

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Target AudienceThis activity is intended for allergists & clinical immunologists, pulmonologists, surgeons, and nurses.

GoalThe goal of this activity is to inform clinicians of recent data regarding the use of biomarkers and biologic therapy in the management of patients with severe asthma.

Learning ObjectivesUpon completion of this activity, participants will:

Have increased knowledge regarding the• Inflammatory pathophysiological underpinnings of asthma

Have greater competence related to• Incorporating new data when selecting biological therapy for appropriate patients with asthma comorbidities,

including nasal polyposis

Credits Available

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Disclosures

Moderator

Michael E. Wechsler, MD Professor of MedicineDivision of Pulmonary, Critical Care and Sleep MedicineNational Jewish Health SystemDenver, Colorado

Disclosure: Michael E. Wechsler, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Genentech, Inc.; GlaxoSmithKline; Mylan Laboratories Inc.; Regeneron Pharmaceuticals, Inc.; Restorbio; Sanofi; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA

Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Regeneron Pharmaceuticals, Inc.; Sanofi; Teva Pharmaceuticals USA

Panelists

Mario Castro, MD Division ChiefPulmonary, Critical Care, and Sleep MedicineThe University of Kansas Health SystemKansas City, Kansas

Mario Castro, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Genentech, Inc.; Sanofi-Aventis; Teva Pharmaceuticals USA; Theravance, Inc.; VIDA

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Genentech, Inc.; GlaxoSmithKline; Regeneron Pharmaceuticals, Inc.; Sanofi; Teva Pharmaceuticals USA

Received grants for clinical research from: AstraZeneca Pharmaceuticals LP; Aventis; Chiesi Pharmaceuticals, Inc. ; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Sanofi

Bradley E. Chipps, MD Medical DirectorCapital Allergy & Disease CenterSacramento, California

Bradley E. Chipps, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; Circassia; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; Sanofi-Genzyme; Teva Pharmaceuticals USA

Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Circassia; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; Sanofi-Genzyme; Teva Pharmaceuticals USA

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CME Reviewer / Nurse PlannerAmy Bernard, MS, BSN, RN-BC, CHCPDirector Accreditation Services, Medscape, LLCDisclosure: Amy Bernard, MS, BSN, RN-BC, CHCP, has disclosed no relevant financial relationships.

Peer ReviewerThis activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Asthma: Integrating Biologic Therapies for Improved Outcomes

Michael E. Wechsler, MD: Hello, I’m Dr Michael Wechsler, professor of medicine in the division of pulmonary, critical care, and sleep medicine at National Jewish Health in Denver, Colorado. Welcome to this program titled, “Asthma: Integrating Biologic Therapies for Improved Outcomes

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Panelists

Michael E. Wechsler, MD: Joining me today are Dr Mario Castro, chief of pulmonary, critical care, and sleep medicine at the University of Kansas School of Medicine, Kansas City, and Dr Bradley Chipps, medical director of Capital Allergy and Disease Center in Sacramento, California.

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Introduction

Michael E. Wechsler, MD: We’re in a very exciting time in the management of asthma with new therapies, new biomarkers, and new opportunities for our patients with severe asthma. Today, we will be bringing you the highlights of new data on biologic therapy to treat asthma that were presented in Madrid.

We’ll be reviewing the relationship between biologic therapy and improvements in asthma control and quality of life in the application of data to real-world clinical practice. This will include data on biomarkers of type-2 (T2) airway inflammation, and biologic therapies for severe asthma and associated comorbidities, such as nasal polyposis and atopic conditions. In the first segment of this program, Dr Mario Castro will discuss new data on biologic therapy for patients with severe asthma.

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New Data on Biologic Therapy in Severe Asthma

Mario Castro, MD, MPH: Hello, I’m Dr Mario Castro, chief of pulmonary and critical care medicine at the University of Kansas. I’m going to be discussing new data on biologic therapy for patients with severe asthma that were presented at the meeting.

Let’s talk first about what was presented in regard to biologic therapy.

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Mepolizumab Safety and Efficacy in Real-World Clinical Practice: REALITI-A Study

Mario Castro, MD, MPH: The first study I’m going to discuss is of the effectiveness and safety of mepolizumab in a real-world clinical practice, the REALITI-A study. In this study, researchers wanted to assess the effectiveness of mepolizumab in patients with severe eosinophilic asthma in a real-world setting. This was a 2-year, prospective, global study looking at patients with severe eosinophilic asthma who were newly prescribed 100-mg mepolizumab subcutaneously. The primary endpoint in this study was clinically significant exacerbations that required oral corticosteroids, or events that led to an emergency room visit or hospitalization.

In addition, the authors tracked exacerbations that required emergency room visits and hospitalizations, as well as the use of maintenance oral corticosteroids.

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Mepolizumab Safety and Efficacy in Real-World Clinical Practice: REALITI-A Study (cont)

Mario Castro, MD, MPH: A total of 368 patients were evaluated and their mean blood eosinophil count was 370 cells/µL.What’s interesting in this real-world study is that 39% of the patients were former or current smokers, and 61% never smoked. That’s quite different compared with our typical randomized controlled trials. Interestingly, 70% of these patients were taking chronic oral corticosteroids.

The researchers found that there was a 70% reduction in clinically significant exacerbations in patients treated with mepolizumab, and a 77% reduction in exacerbations that resulted in a visit to the hospital or emergency room. Lastly, the median oral corticosteroid dose decreased from 10 mg to 5 mg. About a third (34%) of patients stopped taking oral corticosteroids when treated with mepolizumab.

In terms of safety, 14% of patients reported adverse events (AEs), but they were very minor with few serious AEs, and there were no fatal events.

In conclusion, this study shows that in this real-world setting, mepolizumab significantly reduced exacerbations and oral corticosteroid use, similar to what we had seen previously in randomized control trials.

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Effect of Dupilumab on Lung Function in Uncontrolled Moderate-to-Severe Allergic Asthma

Mario Castro, MD, MPH: Let’s talk about the dupilumab study that evaluated the effect of dupilumab in a subset of patients who had an allergic phenotype. Dupilumab blocks 2 of the T2 cytokines, interleukin (IL)-4 and IL-13. This study looked at the subset of patients who had an allergic phenotype defined as serum immunoglobulin E (IgE) of >30 and 1 or more perennial air allergens that were positive in the blood for specific IgE. They found that when dupilumab was used in either the 200-mg dose or the 300-mg dose every 2 weeks it reduced exacerbations and improved lung function in quality of life measures in comparison with placebo.

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Effect of Dupilumab on Exacerbation Rate

Mario Castro, MD, MPH: But let’s look at those same results in the subset of patients who had allergic asthma.

What’s demonstrated in this graph (on the left hand side) is patients who had the criteria for allergic asthma, and then on the right hand side, patients who did not meet that criteria for allergic asthma. The orange bars represent the 200-mg dose, and the blue columns represent the 300-mg dose. What you’ll note is that there was a significant improvement in reducing exacerbations with both the 200-mg dose and the 300-mg dose in patients who met criteria for allergic phenotype.

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Effect of Dupilumab on Lung Function in Uncontrolled Moderate-to-Severe Asthma

Mario Castro, MD, MPH: When we look at mid-flows -- forced expiratory flow (FEF) 25% to 75% -- and when we look at the forced expiratory volume in 1 second-forced vital capacity (FEV1-FVC) ratio, again, there were significant improvements in patients who have that allergic phenotype. There were less dramatic results in those patients who did not have the allergic phenotype.

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Effect of Dupilumab on Lung Function in Uncontrolled Moderate-to-Severe Asthma (cont)

Mario Castro, MD, MPH: In conclusion, this subset analysis from the LIBERTY QUEST study demonstrates that dupilumab improves lung function, both pre-bronchodilator and post-bronchodilator in the mid-flows (FEF 25% to 75%), in patients who were treated with either the 200-mg dose or the 300-mg dose. This effect was consistent in patients who had evidence of allergic inflammation, as well as those without allergic inflammation. We saw this effect early on at week 12, and it was sustained through the end of the study.

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Omalizumab and Mepolizumab vs No Biologic in the Treatment in Severe Asthma

Mario Castro, MD, MPH: Let’s review a study that described the characteristics of patients treated with omalizumab, mepolizumab, or no biologic therapy from the Belgian Severe Asthma Registry.

This study assessed the clinical benefit of omalizumab and mepolizumab on asthma control exacerbation rates in oral corticosteroid use in patients from Belgium’s Severe Asthma Registry. This was an observational study that included more than 1000 patients with severe asthma who had been enrolled since 2009 throughout 24 centers. Of this, longitudinal data were available in 345 patients; of those 345, 57 patients were given mepolizumab, and 59 patients were given omalizumab. The patients who did not receive biologics were used as a comparison group.

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Omalizumab and Mepolizumab vs No Biologic in the Treatment in Severe Asthma (cont)

Mario Castro, MD, MPH: They found that patients who received omalizumab or mepolizumab showed significant improvements in asthma control, as measured by either the Asthma Control Test (ACT) or the Asthma Control Questionnaire (ACQ).

Interestingly, as opposed to mepolizumab, omalizumab significantly decreased expired nitric oxide (FeNO) level. Mepolizumab significantly decreased the oral corticosteroid (prednisone) use from about 8 mg/day to 3 mg/day over that year. A significant oral steroid-sparing effect was seen from mepolizumab. Lastly, a significant decrease in exacerbations was noted in all groups that were observed; the highest decrease was noted in those treated with omalizumab.

In conclusion, in this real-world study from the Belgian Severe Asthma Registry demonstrates that these 2 new biologics, omalizumab and mepolizumab, improve asthma control in exacerbation rates. Mepolizumab, in particular, had an oral corticosteroid-sparing effect.

Next, you’re going to hear from Dr Bradley Chipps, who will be talking about new data on the role of biomarkers in the management of severe asthma.

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Role of Biomarkers in the Management of Severe Asthma

Bradley E. Chipps, MD: Hello, I’m Dr Bradley Chipps, medical director at the Capital Allergy & Respiratory Disease Center in Sacramento, California. Today I’m going to be talking about new data on the role of biomarkers in the management of severe asthma.

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Use of Biomarkers in Patients With Severe Asthma Can Help Extend Pharmacologic Management

Bradley E. Chipps, MD: We’re going to talk about how biomarkers can be used to extend pharmacologic management in patients who have failed Global Initiative in Asthma (GINA) step 4 and 5 treatment. These are data that can be integrated into your clinical practice today and will be very important in educating physicians who treat asthma.

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Severe Concordant Eosinophilic Asthma and IgE Status

Bradley E. Chipps, MD: This abstract, Characterization of a Cohort Asthmatic With Severe Concordant Eosinophilic Disease According to Their IgE Status, discussed the assessment of eosinophilic airway inflammation in IgE and non-IgE immediate severe concordant eosinophilic asthma treated with inhaled corticosteroids and oral corticosteroids. It’s a retrospective study of 139 participants identified as having severe eosinophilic asthma.

These patients had sputum eosinophil counts ≥3% and blood eosinophil counts ≥400/mm3. Atopy was identified by persistence of at least 1 positive specific IgE test > 0.35 kU/L to a common aeroallergen. Total serum IgE was >113 kU/L, which was considered to be elevated.

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Severe Concordant Eosinophilic Asthma and IgE Status (cont)

Bradley E. Chipps, MD: Sixty-seven percent of the patients with eosinophilic asthma had elevated total serum IgE atopy. Patients with non-IgE mediated eosinophilic asthma had late-onset disease, and had more intense eosinophilic airway inflammation. They required more frequent maintenance treatment with oral corticosteroids; however, these patients required a higher dose of methacholine to cause a 20% drop in FEV1.

We concluded that corticosteroid resistance may be a factor in non-IgE-mediated concordant eosinophilic asthma with more severe airway eosinophilic inflammation, despite treatment with inhaled corticosteroids, and a higher burden of oral corticosteroids.

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T2-Biomarker in Severe Asthma: UKSAR

Bradley E. Chipps, MD: The second abstract was a characterization of T2-biomarker low in patients with severe asthma in the UK Severe Asthma Registry (UKSAR). It examined the baseline demographics of T2-biomarker low patients with severe asthma to assess presenting symptoms despite suppression of T2-cytokine pathways with corticosteroids.

The study baseline demographic used characteristics according to European Respiratory Society, American Thoracic Society (ERS/ATS) criteria for severe asthma. Of the 1408 non-smoking participants, the 119 compositing T2-low participants had FeNO ≤25 parts per billion (ppb) and blood eosinophil counts <150/μL. The 613 composite T2-high participants had FeNO ≥25 ppb and blood eosinophil counts >150/μL.

Asthma control and exacerbations 12 months before registration were similar in both groups at the time of enrollment in the study.

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T2-Biomarker in Severe Asthma: UKSAR (cont)

Bradley E. Chipps, MD: T2-low patients were more likely to be Caucasians, have earlier onset of disease, and higher body-mass index (BMI) (32.7 vs 30.2, respectively). T2-low patients had significantly lower total lung capacity and residual volume (102% vs 123%), and less airflow obstruction. FEV1 to FVC ratio was 70% vs 63%, respectively. T2-low patients were more likely to be taking maintenance oral corticosteroids, 60% vs 45%, respectively. While blood eosinophil count was lower than in T2-high patients, it was still elevated and consistent with corticosteroid T2 suppression.

We can conclude that T2-biomarker low patients had higher BMI and more restrictive lung function. They may require additional non-pharmacologic approaches; in part, to evaluate the relationship of extra pulmonary factors, such as obesity and other comorbidities.

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Clinical Response to Benralizumab in Patients With Severe Asthma Eosinophilic Phenotypes

Bradley E. Chipps, MD: Another abstract examined the relationship between severe asthma, eosinophilic phenotypes, and the clinical response to benralizumab at 16 weeks. It assessed differences in efficacy of benralizumab among severe eosinophilic asthma phenotypes including child onset, atopic disease, adult-onset atopic asthma, and adult-onset non-atopic asthma at 16 weeks. The study design was a retrospective review of patients with severe eosinophilic asthma who completed more than 16 weeks of benralizumab treatment.

There were 80 participants divided into 3 sub-phenotypes; 39 participants had child-onset asthma, 24 participants had adult-onset atopic asthma, and 17 participants had adult-onset non-atopic asthma. ACQ-6 and Asthma Quality of Life Questionnaire (AQLQ) were administered. No significant differences were found between the ACQ-6 or the AQLQ questionnaire. FEV1 previous exacerbation frequency or eosinophil count baselines showed no significant differences.

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Clinical Response to Benralizumab in Patients With Severe Asthma Eosinophilic Phenotypes (cont)

Bradley E. Chipps, MD: At 16 weeks, 67% of participants with child-onset asthma, 92% of participants with adult-onset atopic asthma, and 100% of participants with adult-onset non-atopic asthma were exacerbation-free. Significant improvements in the ACQ-6 and the AQLQ questionnaire were not significant between the groups.

In previously published literature, atopic and non-atopic patients were not predictors of response to therapy. Previously evaluated enhanced response has been identified in patients with FVC less than 65%, oral corticosteroid use, nasal polyps, increased rate of exacerbation, eosinophil count > 300 call/mm3 in late-onset disease.

We concluded that of the severe eosinophilic asthma sub-phenotypes, adult-onset atopic and adult-onset non-atopic were more likely to be exacerbation free at 16 weeks of benralizumab therapy as compared with child-onset severe eosinophilic asthma. The overall significant improvements in asthma control in quality of life were present in all groups.

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Severe Asthma Phenotypes: T2 High and T2 Low

Bradley E. Chipps, MD: The analysis of phenotypes in a group of severe asthma patients was also studied in a group of 50 female patients with severe asthma who were included in a post-factor study. The patients were divided into 2 groups based upon the inflammatory phenotypes. T2-high asthma group (n=26) was defined by the presence of blood eosinophils ≥ 400 mm³, and/or sputum eosinophils > 2%, and/or a total IgE > 100 IU/mL, and/or FeNO ≥ 25 ppb.

The absence of these characteristics were consistent with T2-low asthma group (n=24). There were no significant differences between the median age of asthma in both phenotypes.

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Severe Asthma Phenotypes: T2 High and T2 Low (cont)

Bradley E. Chipps, MD: T2-high asthma was more likely to be atopic (69% vs 37%). Near-fatal asthma was more frequent then the T2-high asthma phenotype (84% vs 58%). The T2-low asthma group reported more daily asthma symptoms with ACTs (14.8% vs 16.5%). The T2-low asthma group had lower FEV1 values, although this difference was not statistically significant.

Fixed airway obstructions were common in the T2-low asthma group (83% vs 53%). T2-high asthma group were treated more frequently with systemic corticosteroids (34% vs 20%). Among T2-high asthma group, 24% were eligible for anti-IgE therapy.

We can conclude that T2-high asthma is characterized by more near-fatal asthma events, and requires higher doses of corticosteroids to be controlled. T2-low asthma seems to be linked to more severe asthma symptoms and worse lung function.

We’re going to hear from Dr Mario Castro who will discuss new data on the biologic therapy for patients with severe asthma and comorbidities.

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New Data on Biologic Therapy for Severe Asthma and Comorbidities and Summary

Dr Castro: Hello. I’m Dr Mario Castro. I’m the chief of pulmonary medicine critical care medicine at University of Kansas in Kansas City, Kansas. I’m going to talk about some new data regarding patients who were treated with biologic therapy who had underlying severe asthma and significant comorbidities. Let’s look at these results, which demonstrate the importance of obtaining patient histories as well as understanding what underlying comorbidities patients have in addition to their underlying severe asthma.

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Dupilumab in Severe Chronic Rhinosinusitis With Nasal Polyps With/Without NSAID-ERD

Dr Castro: The first study we will be reviewing is the dupilumab efficacy study of patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) with and without nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). These were pivotal results from the phase 3 SINUS-24 and SINUS-52 trials. The aim of this study was to evaluate dupilumab’s treatment effects in patients with severe CRSwNP with or without NSAID-ERD who were being treated with intranasal mometasone furoate throughout the trial.

These were patients with chronic rhinosinusitis nasal polypoids who were evaluated for underlying nasal polyps using the nasal polyps score, the nasal congestion score, the disease severity score (a visual analog score), the computed tomography (CT) Lund-Mackay score, the sinus opacification score, a smell test, a symptom score, and the Sino-nasal Outcome Test (SNOT)-22 questionnaire. In this study, there was a significant improvement in the nasal polyps score, the disease severity score, the CT Lund-Mackay score, and their total symptom score, as well as their loss of smell. In addition, SNOT-22 score was improved. These are all-important measures -- quantitative measures -- of the impact of dupilumab on the upper airway.

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Dupilumab in Severe Chronic Rhinosinusitis With Nasal Polyps With/Without NSAID-ERD (cont)

Dr Castro: They found that use of dupilumab improved the nasal symptom scores, the disease severity scores, the scores from CT scans, the questionnaires (SNOT-22), the total symptom score and the loss of smell. They also found that the need for systemic corticosteroids or surgery was significantly reduced in patients with NSAID-ERD by 79%, and without NSAID-ERD by 73%. The most common AEs noted in this study were nasal pharyngitis, headache, worsening nasal polyposis and asthma, epistaxis, and injection-site erythema, all occurring with a slightly higher frequency in comparison to the placebo-treated group.

In conclusion, these results from the SINUS-24 and SINUS-52 studies show that dupilumab is a powerful biologic that improves measurable upper-airway symptoms using a variety of different clinical measures and questionnaires, but also improves the actual visualization of polyps using endoscopy and radiologic measures from CT of the sinuses. This effect was very similar in patients with and without NSAID-ERD. Dupilumab was well tolerated.

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Dupilumab in Patients With Severe Chronic Rhinosinusitis With Nasal Polyps and NSAID-ERD

Dr Castro: The next abstract focuses on the effect in patients with underlying chronic rhinosinusitis on their lower airway disease. We’ll also talk about some other measures from the SINUS-24 and SINUS-52 phase 3 trials.

The aim of the study was to assess the effect of dupilumab vs placebo in upper- and lower-airway outcomes in patients with chronic rhinosinusitis and nasal polyposis with and without underlying NSAID-ERD who were also taking background therapy with mometasone nasal spray.

The study design included an assessment of exacerbations induced by NSAIDs in patients with underlying chronic rhinosinusitis and included measures of peak nasal inspiratory flow, lung function, asthma control, urinary leukotriene E4, and serum total IgE. It was a combination of kind of flow in the upper airways, impact on the lower airway as measured by lung function and measured by asthma control, and biomarkers that were measured in this study.

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Dupilumab in Patients With Severe Chronic Rhinosinusitis With Nasal Polyps and NSAID-ERD (cont)

Dr Castro: Let’s look at the results from this study. When we looked at the results from baseline to week 24, dupilumab significantly improved lung function by 0.26 L, which is consistent with earlier trials from the QUEST and VENTURE studies, but also improved peak nasal inspiratory flow by 52 L/min, a significant improvement. When we looked at the biomarkers from this study, urinary leukotriene E4 (LTE4) was also significantly decreased by 57% in the SINUS-24 study and by significantly more than 70% in the SINUS-52 studies depending, again, on which dose of the drug the patient was taking.

The second biomarker that was evaluated was serum total IgE, and this also decreased by a median of 60%. AEs included nasal pharyngitis, headache, worsening nasal polyposis and asthma, epistaxis, and injection-site erythema.

In conclusion, what we found in this study that evaluated the lower airway in patients with underlying chronic rhinosinusitis and nasal polyposis was that dupilumab significantly improved airway symptomatology in addition to upper airway functions, such as the nasal inspiratory flow. This occurred in patients with NSAID-ERD, as well as those without. Dupilumab was well tolerated in these studies.

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Fezakinumab: Novel Anti-IL-22 Antibody Potential Role in Asthma

Dr Castro: Let’s talk about a new monoclonal antibody called fezakinumab, which is an investigational anti-IL-22 antibody. In this study, they looked at the gene signature in patients who had atopic dermatitis and what their gene signature was in skin tissue after treatment with fezakinumab. They then evaluated that gene signature in the blood and airway specimens from patients with asthma from the U-BIOPRED cohort. They found that fezakinumab, this anti-IL-22 monoclonal antibody, reduced the gene signature of atopic dermatitis in the blood of these patients from the U-BIOPRED cohort in the asthmatic population. This is important.

This suggests that there may be a subset of patients with asthma that may respond to this anti-IL-22 antibody. Again, identification of these phenotypes is very important in advancing our knowledge about the treatment of asthma in these patients. In this subset, this gene signature for atopic dermatitis suggests it may be a phenotype to target, and that we could use this monoclonal antibody in future studies.

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Efficacy of Omalizumab in Patients With Severe Asthma and Multiple Allergic Comorbidities

Dr Castro: Let’s move on to a monoclonal antibody that’s been with us for 16-plus years: anti-IgE therapy with omalizumab. This was evaluated in adults and pediatrics that met criteria for severe allergic asthma in the STELLAR study.

This particular subset analysis looked at patients who participated in the STELLAR study who had multiple allergic comorbidities. This was defined by having 2 or more allergic comorbidities and those with multiple allergic comorbidities were compared with patients with fewer than 2 allergic comorbidities. The effect of omalizumab was evaluated at 4 to 6 months via physician evaluation, using the Global Evaluation of Treatment Effectiveness (GETE) score, exacerbations, or a combination of GETE score and exacerbations.

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Efficacy of Omalizumab in Patients With Severe Asthma and Multiple Allergic Comorbidities (cont)

Dr Castro: They found that multiple allergic comorbidities were more common in children than in adults (47% vs 14 %, respectively).

The innate age of initiation of omalizumab was significantly lower in patients who had multiple allergic comorbidities, 32 years vs 46 years. Patients with multiple allergic comorbidities had an even greater response to omalizumab in comparison to those without multiple comorbidities. Eighty-one percent of patients had a higher response to omalizumab compared with 66%, respectively, based on physician evaluation. When we looked at exacerbations, again, those were much greater in patients with multiple allergic comorbidities in comparison to those without. This suggests that the subset of patients with the underlying phenotype of multiple allergic comorbidities has an enhanced response to omalizumab.

This was even seen in a much greater percentage of children. We can use omalizumab. It’s approved down to age 6 years, which includes a significant pediatric population. This important historical feature should prompt us to obtain the history of our patients during our consideration of which biologic to use. This underlying multiple allergic comorbidity may predict patients’ response to omalizumab.

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Summary

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Concluding Remarks

Dr Wechsler: What we’ve learned today from the meeting in Madrid is that there are promising data in the management of severe asthma that can guide treatment decisions, and help promote better asthma control and quality of life. These are very exciting times for patients with severe asthma.

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Thank You

Dr Wechsler: Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

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AbbreviationsACT = Asthma Control TestACQ = Asthma Control QuestionnaireACQ-6 = Asthma Control Questionnaire-6AD = atopic dermatitisAE = adverse eventAQLQ = Asthma Quality of Life QuestionnaireAR = allergic rhinitisBMI = body mass indexBSAR = Belgian Severe Asthma RegistryCRSwNP = chronic rhinosinusitis with nasal polypsCT-LMK = computed tomography Lund–MackayED = emergency departmentFeNO = fractional exhaled nitrous oxide FEV1 = forced expiratory volume in 1 secondFVC = forced vital capacity GETE = Global Evaluation of Treatment EffectivenessGINA = Global Initiative for Asthma ICS = inhaled corticosteroidIgE = immunoglobulin EIL-4 = interleukin-4IL-5 = interleukin-5IL-13 = interleukin-13 IL-22 = interleukin-22LABA = long-acting beta-antagonistLTRA = leukotriene receptor antagonistMAC = multiple allergic comorbiditiesNC = nasal congestionNPS = nasal polyp scoreNSAID = nonsteroidal anti-inflammatory drugNSAID-ERD = nonsteroidal anti-inflammatory drug-exacerbated respiratory diseaseOCS = oral corticosteroidPBO = placeboPNIF = peak nasal inspiratory flowppb = parts per billion RV = residual volumeSC = subcutaneousSEA = severe eosinophilic asthmaSCS = systemic corticosteroidsSNOT-22 = Sino-nasal Outcome TestTLC = total lung capacityTSS = total symptom scoreULTE4 = urinary leukotriene 4UPSIT= University of Pennsylvania Smell Identification TestVAS = visual analogue scale

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References

1. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019. doi: 10.1016/S0140-6736(19)31881-1. [Epub ahead of print]

2. Badi Y, Pavel AB, Riley JH, et al. Is fezakinumab, an anti-IL-22 antibody, a putative novel therapy for a subset of severe asthma? Presentation at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Presentation 1606.

3. Busby J, Pfeffer PE, Jackson DJ, et al. Characteristics of T2-biomarker low severe asthma patients in the UK Severe Asthma Registry. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 2788.

4. Castro M, Corren J, Casale TB, et al. Dupilumab Effect on lung function in patients with uncontrolled, moderate-to-severe asthma with an allergic phenotype. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 540.

5. Chipps B, Newbold P, Hirsch I, et al. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018;120:540-511.

6. Corren J, et al. Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma. J Aller Clin Immun-Pract. (2019). doi: 10.1016/j.jaip.2019.08.050. [Epub ahead of print]

7. Fitzgerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIRROCCO and CALIMA studies. Lancet Repir Med. 2018;6:51-64.

8. Gerday S, Schleich F, Henket M, et al. Characterisation of a cohort of asthmatics with severe concordant eosinophilic disease according to their IgE status. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 5028.

9. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention (Update 2019). 2019.10. Harrison T, Canonica GW, Gemzoe K, et al. Effectiveness and safety of mepolizumab in real-world clinical practice: the REALITI-A

study. Presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Abstract 2104.

11. Jackson D, Roxas C, Green L, et al. The relationship between severe asthma eosinophilic phenotypes and the clinical response to benralizumab at 16 weeks. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Abstract 2547.

12. Just J, Thonnelier C, Lecocq B, et al. Is Efficacy of omalizumab in adult and pediatric severe allergic asthma according to presence of multiple allergic comorbidities: evidence from the STELLAIR study. Poster Presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 543.

13. Laidlaw TM, Mullol J, Canonica G, et al. Dupilumab improves upper and lower airway outcomes in chronic rhinosinusitis with nasal polyps with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease: pooled results from SINUS-24, SINUS-52 phase 3 trials. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 539.

14. Louhaichi S, Roxas C, Green L, et al. Analysis of phenotypes in a group of severe asthma. Poster presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Poster 2547.

15. Mullol J, Laidlaw TM, Amin N, et al. Dupilumab (DPL) efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) with/without nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD): SINUS-24, SINUS-52 trials. Clinical trial presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Abstract 3783.

16. Pavord ID, Fitzgerald JM, Brusselle G, et al. Dupilumab efficacy in type 2 inflammatory asthma: Liberty Asthma QUEST study. Presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Abstract 3807.

17. Schleich F, Brusselle G, Hanon S, et al. Characteristics of severe asthmatics treated with omalizumab, mepolizumab, or no biotherapy. Data from the Belgian Severe Asthma Registry. Presented at: European Respiratory Society International Congress 2019; September 28-October 2, 2019; Madrid, Spain. Abstract 5353.

asthma: integrating biologic therapies for improved

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