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Clinically Significant Improvements in Asthma Patient-Reported Outcomes: Results from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) Study
28
New Oral Treatments for Asthma through TissueSpecific Modulation of the GABAA Receptor
Leggy Arnold1, Gloria Forkuo1, Amanda Nieman1, Olivia B. Yu1, Margaret L. Guthrie1, Revathi Kodali1, Nina Yuan1, Rajwana Jahan1, Michael S. Stephen1, Charles W. Emala2, Gene T. Yocum3, James M. Cook1, and Mitchell H. Grayson, MD, FAAAAI4; 1University of Wisconsin Milwaukee, Milwaukee, WI, 2Columbia University, New York, 3Columbia Univeristy, New York, NY, 4700 Children’s Drive, Nationwide Children’s Hospital / The Ohio State University, Columbus, OH. RATIONALE: This study addresses the unmet need for an oral, safe, nonsteroidal asthma treatment. The hypothesis is that GABAARs in airway smooth muscle (ASM) and inflammatory cells can be targeted by subtype-selective GABAAR modulators to tissue-selectively induce ASM relaxation and immunosuppression. METHODS: New drug candidates were characterized by electrophysiology and microsome, S9, and blood plasma stability assays. Pharmacokinetic studies in mice are used to identify in vivo stability and distribution. Murine pharmacodynamic models are used to quantify sensorimotor effects (rotarod), disease specific airway hyperresponsiveness, airway mucus production, and airway eosinophilia. ASM muscle relaxation was tested in ex vivo lung tissue. The immune modulatory effect of subtype-selective GABAAR ligands was evaluated by flow cytometry. RESULTS: A a5 subtype-selective GABAAR ligand showed excellent PK when given orally. The compound did not cross the BBB, thus no sensorimotor effects were observed. The compound inhibited eosinophilia and reduced the number of inflammatory cells. Significant muscle relaxation was observed ex vivo in trachea rings and reduced airway hyperresponsiveness was observed in mice. Importantly, this is the first oral treatment for asthma specifically targeting muscle relaxation and inflammation. In addition, a novel a4 subtype-selective GABAAR ligand was identified with equally excellent stability in vitro and in vivo. Reduced airway hyperresponsiveness was observed at low concentrations of methacholine. The anti-inflammatory properties were significant but immune cell populations were regulated differently. CONCLUSIONS: a4 and a5-selective GABAAR modulators have a great potential as novel orally active drug candidates for asthma to alleviate symptoms of airway hyperresponsiveness mediated by ASM constriction, hypereosinophilia, and inflammation.
29
Clinically Significant Improvements in Asthma Patient-Reported Outcomes: Results from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) Study
Erika G. Gonzalez-Reyes, MD1, Allan T. Luskin, MD2, William Busse, MD3, Thomas B. Casale, MD, FAAAAI4, Bradley E. Chipps, MD5, Evgeniya Antonova, MS, PhD6, Susan L. Limb, MD6, Benjamin L. Trzaskoma, MS6, Noelle M. Griffin, PhD6, and Robert S. Zeiger, MD, PhD, FAAAAI7; 1Children’s Hospital of San Antonio- Baylor College of Medicine, San Antonio, TX, 2HealthyAirways, Madison, WI, 3 University of Wisconsin School of Medicine and Public Health, Madison, WI, 4University of South Florida, Tampa, FL, 5Capital Allergy and Respiratory Disease Center, Sacramento, CA, 6Genentech, Inc., South San Francisco, CA, 7Kaiser Permanente Southern California, San Diego and Pasadena, CA. RATIONALE: Real-world data on patient-reported outcomes in asthma patients receiving omalizumab treatment are limited. This study aims to bridge that gap. METHODS: PROSPERO, a US-based, multicenter, prospective, 12_ 12 years old with asthma month, observational study, enrolled patients > who initiated omalizumab therapy between 6/2013-3/2015 (clinicaltrials.gov: NCT01922037). At baseline and throughout the study, patients completed the following validated questionnaires: Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), Work
Productivity and Activity Impairment (WPAI)-Asthma Questionnaire, and Mini Rhinoconjunctivitis Quality of Life Questionnaire (miniRQLQ). Changes from baseline at month 12 are reported for each questionnaire. RESULTS: Among 806 enrolled patients, 622 (77.2%) completed the study. Patients were primarily female (63.5%), white (70.3%), obese (48.5%), diagnosed with moderate (48.1%) or severe (47.8%) asthma and _2 exacerbations in the 12 never smoked (65%); 61% of patients reported > months prior to enrollment. At baseline, patients reported mean [SD] scores: ACT (13.9 [5.0]), AQLQ (4.0 [1.4]), miniRQLQ (2.7 [1.4]), and % WPAI Overall Work Impairment (33.5 [28.7]), and % Daily Activity Impairment (47.7 [28.9]). At the end of the study patients reported clinically meaningful mean [SD] changes from baseline in ACT (4.4 [4.9]), AQLQ (1.3 [1.3]), and miniRQLQ (-1.0 [1.3]) and all WPAI domains, including % Overall Work Impairment (-16.4 [29.6]) and % Daily Activity Impairment (-20.80 [32.4]). CONCLUSIONS: In a real world setting, patients receiving omalizumab reported at month 12, clinically meaningful improvement from baseline in asthma control, asthma- and rhinoconjunctivitis-related quality of life, and decline in work and daily activity impairment.
30
Meta-analysis of Mepolizumab Global Studies Suggest Consistent Therapeutic Response Across a Range of Demographic Sub-groups
Steven W. Yancey, MS1, Necdet B. Gunsoy2, Eric S. Bradford1, Frank C. Albers1, Charlene M. Prazma, PhD1, Richard Follows3, Oliver N. Keene3, and Ian Pavord4; 1GSK, Research Triangle Park, NC, 2GSK, Uxbridge, United Kingdom, 3GSK, Stockley Park, United Kingdom, 4University of Oxford, Oxford, United Kingdom. RATIONALE: A retrospective analysis was conducted to explore treatment responses to mepolizumab across a broad range of subgroups with severe eosinophilic asthma (SEA). METHODS: A meta-analysis of two randomized, double-blind, placebocontrolled studies (N51192; MEA112997/MEA115588) with mepolizumab or placebo plus standard of care given every 4 weeks to SEA patients treated with high dose ICS plus a controller with or without maintenance _2 exacerbations in the previous year and oral corticosteroids, a history of > evidence of eosinophilic inflammation. This post-hoc analysis was conducted using a negative binomial regression model, accounting for study. All mepolizumab doses were combined for this analysis. RESULTS: The overall ratio of exacerbation rates with mepolizumab (n5846) compared with placebo (n5346) was 0.53 (95% CI: 0.44 to 0.62, p<0.001). Among females (n5715) and males (n5477), rate ratios were 0.56 (0.45, 0.70) and 0.45 (0.34, 0.60) respectively. Among AfricanAmericans/Africans (n539), Asian (n5141) and Whites (n51004), rate ratios were 0.61 (0.24, 1.58), 0.39 (0.25, 0.61) and 0.55 (0.45, 0.66), respectively. Among adolescent patients (ages 12–17) in MEA115588 (n525), the rate ratio was 0.68 (0.17, 2.68). The safety profile was generally comparable across the subgroups. CONCLUSIONS: Sub-group analysis showed consistent response in the reduction of clinically significant exacerbations. No unique safety signals emerged from the sub-groups. These post-hoc analyses suggest that the safety and efficacy profile of mepolizumab is consistent across a broad range of sub-groups, indicating that an eosinophilic phenotype in severe asthma identifies a common endotype that is therapeutically responsive to targeting IL-5 and reducing eosinophilic inflammation. Funding: GSK(NCT01000506/NCT01691521).
SATURDAY
Abstracts AB9
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2
New Oral Treatments for Asthma through TissueSpecific Modulation of the GABAA Receptor
Leggy Arnold1, Gloria Forkuo1, Amanda Nieman1, Olivia B. Yu1, Margaret L. Guthrie1, Revathi Kodali1, Nina Yuan1, Rajwana Jahan1, Michael S. Stephen1, Charles W. Emala2, Gene T. Yocum3, James M. Cook1, and Mitchell H. Grayson, MD, FAAAAI4; 1University of Wisconsin Milwaukee, Milwaukee, WI, 2Columbia University, New York, 3Columbia Univeristy, New York, NY, 4700 Children’s Drive, Nationwide Children’s Hospital / The Ohio State University, Columbus, OH. RATIONALE: This study addresses the unmet need for an oral, safe, nonsteroidal asthma treatment. The hypothesis is that GABAARs in airway smooth muscle (ASM) and inflammatory cells can be targeted by subtype-selective GABAAR modulators to tissue-selectively induce ASM relaxation and immunosuppression. METHODS: New drug candidates were characterized by electrophysiology and microsome, S9, and blood plasma stability assays. Pharmacokinetic studies in mice are used to identify in vivo stability and distribution. Murine pharmacodynamic models are used to quantify sensorimotor effects (rotarod), disease specific airway hyperresponsiveness, airway mucus production, and airway eosinophilia. ASM muscle relaxation was tested in ex vivo lung tissue. The immune modulatory effect of subtype-selective GABAAR ligands was evaluated by flow cytometry. RESULTS: A a5 subtype-selective GABAAR ligand showed excellent PK when given orally. The compound did not cross the BBB, thus no sensorimotor effects were observed. The compound inhibited eosinophilia and reduced the number of inflammatory cells. Significant muscle relaxation was observed ex vivo in trachea rings and reduced airway hyperresponsiveness was observed in mice. Importantly, this is the first oral treatment for asthma specifically targeting muscle relaxation and inflammation. In addition, a novel a4 subtype-selective GABAAR ligand was identified with equally excellent stability in vitro and in vivo. Reduced airway hyperresponsiveness was observed at low concentrations of methacholine. The anti-inflammatory properties were significant but immune cell populations were regulated differently. CONCLUSIONS: a4 and a5-selective GABAAR modulators have a great potential as novel orally active drug candidates for asthma to alleviate symptoms of airway hyperresponsiveness mediated by ASM constriction, hypereosinophilia, and inflammation.
29
Clinically Significant Improvements in Asthma Patient-Reported Outcomes: Results from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) Study
Erika G. Gonzalez-Reyes, MD1, Allan T. Luskin, MD2, William Busse, MD3, Thomas B. Casale, MD, FAAAAI4, Bradley E. Chipps, MD5, Evgeniya Antonova, MS, PhD6, Susan L. Limb, MD6, Benjamin L. Trzaskoma, MS6, Noelle M. Griffin, PhD6, and Robert S. Zeiger, MD, PhD, FAAAAI7; 1Children’s Hospital of San Antonio- Baylor College of Medicine, San Antonio, TX, 2HealthyAirways, Madison, WI, 3 University of Wisconsin School of Medicine and Public Health, Madison, WI, 4University of South Florida, Tampa, FL, 5Capital Allergy and Respiratory Disease Center, Sacramento, CA, 6Genentech, Inc., South San Francisco, CA, 7Kaiser Permanente Southern California, San Diego and Pasadena, CA. RATIONALE: Real-world data on patient-reported outcomes in asthma patients receiving omalizumab treatment are limited. This study aims to bridge that gap. METHODS: PROSPERO, a US-based, multicenter, prospective, 12_ 12 years old with asthma month, observational study, enrolled patients > who initiated omalizumab therapy between 6/2013-3/2015 (clinicaltrials.gov: NCT01922037). At baseline and throughout the study, patients completed the following validated questionnaires: Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), Work
Productivity and Activity Impairment (WPAI)-Asthma Questionnaire, and Mini Rhinoconjunctivitis Quality of Life Questionnaire (miniRQLQ). Changes from baseline at month 12 are reported for each questionnaire. RESULTS: Among 806 enrolled patients, 622 (77.2%) completed the study. Patients were primarily female (63.5%), white (70.3%), obese (48.5%), diagnosed with moderate (48.1%) or severe (47.8%) asthma and _2 exacerbations in the 12 never smoked (65%); 61% of patients reported > months prior to enrollment. At baseline, patients reported mean [SD] scores: ACT (13.9 [5.0]), AQLQ (4.0 [1.4]), miniRQLQ (2.7 [1.4]), and % WPAI Overall Work Impairment (33.5 [28.7]), and % Daily Activity Impairment (47.7 [28.9]). At the end of the study patients reported clinically meaningful mean [SD] changes from baseline in ACT (4.4 [4.9]), AQLQ (1.3 [1.3]), and miniRQLQ (-1.0 [1.3]) and all WPAI domains, including % Overall Work Impairment (-16.4 [29.6]) and % Daily Activity Impairment (-20.80 [32.4]). CONCLUSIONS: In a real world setting, patients receiving omalizumab reported at month 12, clinically meaningful improvement from baseline in asthma control, asthma- and rhinoconjunctivitis-related quality of life, and decline in work and daily activity impairment.
30
Meta-analysis of Mepolizumab Global Studies Suggest Consistent Therapeutic Response Across a Range of Demographic Sub-groups
Steven W. Yancey, MS1, Necdet B. Gunsoy2, Eric S. Bradford1, Frank C. Albers1, Charlene M. Prazma, PhD1, Richard Follows3, Oliver N. Keene3, and Ian Pavord4; 1GSK, Research Triangle Park, NC, 2GSK, Uxbridge, United Kingdom, 3GSK, Stockley Park, United Kingdom, 4University of Oxford, Oxford, United Kingdom. RATIONALE: A retrospective analysis was conducted to explore treatment responses to mepolizumab across a broad range of subgroups with severe eosinophilic asthma (SEA). METHODS: A meta-analysis of two randomized, double-blind, placebocontrolled studies (N51192; MEA112997/MEA115588) with mepolizumab or placebo plus standard of care given every 4 weeks to SEA patients treated with high dose ICS plus a controller with or without maintenance _2 exacerbations in the previous year and oral corticosteroids, a history of > evidence of eosinophilic inflammation. This post-hoc analysis was conducted using a negative binomial regression model, accounting for study. All mepolizumab doses were combined for this analysis. RESULTS: The overall ratio of exacerbation rates with mepolizumab (n5846) compared with placebo (n5346) was 0.53 (95% CI: 0.44 to 0.62, p<0.001). Among females (n5715) and males (n5477), rate ratios were 0.56 (0.45, 0.70) and 0.45 (0.34, 0.60) respectively. Among AfricanAmericans/Africans (n539), Asian (n5141) and Whites (n51004), rate ratios were 0.61 (0.24, 1.58), 0.39 (0.25, 0.61) and 0.55 (0.45, 0.66), respectively. Among adolescent patients (ages 12–17) in MEA115588 (n525), the rate ratio was 0.68 (0.17, 2.68). The safety profile was generally comparable across the subgroups. CONCLUSIONS: Sub-group analysis showed consistent response in the reduction of clinically significant exacerbations. No unique safety signals emerged from the sub-groups. These post-hoc analyses suggest that the safety and efficacy profile of mepolizumab is consistent across a broad range of sub-groups, indicating that an eosinophilic phenotype in severe asthma identifies a common endotype that is therapeutically responsive to targeting IL-5 and reducing eosinophilic inflammation. Funding: GSK(NCT01000506/NCT01691521).
SATURDAY
Abstracts AB9
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2