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Biologics in Asthma

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Biologics in Asthma: Present andPresenter Future of Flavia Hoyte,Reproduction MD Associate Professorfor of Medicine FellowshipProperty Training Program Director DivisionNot of Allergy and Immunology National Jewish Health and University of Colorado Disclosures Clinical investigator for GSK, TEVA, and Astra‐ Zeneca. Presenter of Reproduction for Property Not Learning objectives 1. Discuss current approaches to the management of moderate to severe asthma in adult patients. Presenter of 2. Describe new and emergingReproduction biologics for for the managementProperty of moderate to severe asthma. Not Asthma: A Highly Prevalent and Often Inadequately Controlled Disease 24+ million people in the US have asthma.1 17.72 million adults have asthma.Presenter1 of Reproduction 8.86 million adults havefor inadequately 39% of adults with Propertycontrolled asthma.2 1.33 million adults active asthma use Not have inadequately long‐term control controlled asthma medications.3 with eosinophilia.4 1. Centers for Disease Control and Prevention (CDC). Most Recent Asthma Data (2014 data). Accessed June 2016. 2. CDC. Uncontrolled asthma among persons with current asthma. Accessed June 2016. 3. CDC. Use of long‐term control medication among persons with active asthma. Accessed June 2016. 4. McGrath KW et al. Am J Respir Crit Care Med. 2012;185:612‐619. Paradigm Shift to a More Personalized Approach to Asthma Therapy Presenter of Reproduction for Property Not Dunn RM and Wechsler ME. Clinical Pharmacology and Therapeutics 2015; 97(1): 55‐65. Immunopathology of Asthma Presenter of Reproduction for Property Not Pelaia G, et al. Mediators Inflamm 2015:879783. doi: 10.1155/2015/879783. Epub 2015 Mar 23. Presenter of Reproduction for Property Not Katial et al. Currently available biologic agents • Targeting IgE – Omalizumab (approved 2003) Presenter • Targeting eosinophilsof – Monoclonal antibody against IL‐5 • Mepolizumab (approvedReproduction 2015) • Reslizumab (approvedfor 2016) Property – Monoclonal antibodyNot against IL‐5R • Benralizumab (approved 2017) Presenter of Reproduction for Property Not Anti OmalizumabIgE‐ Omalizumab may be more effective in reducing exacerbations for high type 2 biomarker groups Presenter of Reproduction for Property Not Hanania et al. 2013 Presenter of Reproduction for Property Not Hanania et al. Allergy 2018 Anti IL‐5 Presenter Mepolizumabof (IL‐5) ReslizumabReproduction (IL‐5) for BenralizumabProperty (IL‐5R) Not Mepolizumab: DREAM trial Inclusion criteria One of the following: • sputum eos >3%, • FeNO>50, • blood eos >300, Presenter • deterioration of asthma of after <25% reduction in ICS Reproduction or OCS for AND Property • >2 asthma exacerbationsNot in previous year Pavord I, et al. Lancet 2012;380:651–9. Mepolizumab: Reduction of exacerbations & OCS Presenter MENSA: SIRIUS: Exacerbation of Oral Steroid‐ ‐reduction reduction Study ReproductionStudy for Property Not Ortega NEJM 2014 Bel NEJM 2014 DREAM and MENSA: Post‐hoc Analysis Exacerbation Rate Reduction Correlates With Baseline Blood Eosinophil Levels All mepolizumab doses (75 mg, 250 mg, 750 mg IV: and 100mg SQ) combined for analysis Intention‐to‐treat population, n = 344 placebo, n = 841 mepolizumab) Favors Mepolizumab Favors Placebo Presenter Rate Ratio [95% CI] ≥150 cells/mcL of52% reduction 0.48 [0.39, 0.58] ≥300 cells/mcL 59% reduction 0.41 Reproduction [0.33, 0.51] ≥400 cells/mcL for66% reduction 0.34 Property [0.27, 0.44] ≥500 cells/mcL Not70% reduction 0.30 [0.23, 0.40] 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2.0 Ortega et al. Lancet Respir Med 2016. Mepolizumab Response Inversely Correlates with Bronchodilator Reversibility Presenter of Reproduction for Property Not Pavord I et al. Thorax 2010;65:370. MUSCA: Mepolizumab Improves QOL SGRQ = St. George’s Respiratory Questionnaire Presenter of Reproduction for Property Not Chupp GL et al. Lancet Respir Med 2017; 390‐400. Reslizumab BREATH Program Eosinophil Key Objectives Inclusion Criteria Study Design & Outcomes Asthma 16‐week FEV1 –study 3084 Eosinophils Primary— 3 mg/kg IV, ages 18‐65, n = 496 4 Level lung function Unselected 16‐week FEV1 –study 3081 3 mg/kg IV and 0.3 mg/kg,Presenter ages 12‐75, Primary— ofn = 315 lung function1,2 52‐week exacerbation and FEV1 – study 3082 Asthma with 3 mg/kg IV, agesReproduction 12‐75, n = 489 Primary— Elevated exacerbation3 Eosinophils 52‐weekfor exacerbation –study 3083 (≥400) Property3 mg/kg IV, ages 12‐75, n = 464 OpenNot label safety extension‐ study 3085 Primary— Enrolled patients from 3081, 3082, 3083 long‐term safety 3 mg/kg IV, ages 12‐75, n = 1051 1. Bjermer L et al. Eur Resp J. 2014;44(suppl 58):P299. 2. Maspero J et al. Ann Allergy Asthma Immunol. 2014:a21. 3. Castro M et al. Lancet Respir Med. 2015;3(5):355-66. 4. Corren J et al. Eur Resp J. 2014;44(suppl 58):4673. Presenter of Reproduction for Property Not Reslizumab: Reduction in Exacerbations Presenter of Reproduction for Property Not Presenter of Reproduction for Property Not Benralizumab: Mechanism Benralizumab: Effect on Exacerbations Presenter of Reproduction for Property Not FitzGerald J et al. Lancet 2016; 388: 2128–41. Bleecker E et al. Lancet 2016; 388: 2115–27. Benralizumab: Reduction in Exacerbations SIROCCO CALIMA Presenter of Reproduction for Property Not Bleecker E et al. Lancet 2016; 388: 2115–27. FitzGerald J et al. Lancet 2016; 388: 2128–41. Benralizumab: Oral steroid dose & time to first exacerbation Presenter of Reproduction for Property Not Nair P et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1703501 Presenter of Reproduction for Property Not Katial et al. Biologic agents in the pipeline • Targeting both IL‐4 and IL‐13 via IL‐4Rα, a shared receptor component for both cytokines – Dupilumab Presenter • Approved for atopic dermatitisof 3/2017 • Phase 3 OCS reducing study, completed 11/2017 • Phase 3 efficacy, safety,Reproduction & tolerability in severe asthma, completed 11/2017for (primary outcome: exacerbation Property rate, pre‐BD FEV1 change) Not • Phase 3 age 6‐12, actively recruiting Biologic agents in the pipeline • Targeting IL‐13 (phase 3 trials completed, mixed results) – Lebrikizumab Presenter – Tralokinumab of Reproduction • Targeting TSLP (phasefor 2b results published, phase 3 trialsProperty starting up) Not – AMG157, tezepelumab Anti IL‐4Rα Presenter Dupilumabof Reproduction for Property Not Presenter of Reproduction for Property Not Wenzel, S. N Engl J Med. 2013, 368:2455‐2466. Dupilumab & Annualized Severe Exacerbation Rate Eos ≥ 300 cells/µL 1.4 –66% –35% –71% –81% 95% CI 1.2 0.57, 1.90 1.0 95% CI 0.8 0.36, 1.29 * * 0.6 95% CI ** 0.16, 0.81 95% CI 0.4 0.13, 0.68 95% CI *P < 0.05, **P < 0.01, ***P < 0.001 vs placebo. 0.08, 0.52 0.2 Adjusted annualized severe 0 Presenterexacerbation rate, estimate (95% CI) Placebo 200 mg 300 mg 200 mg 300 mg (n = 68) q4w q4w q2w q2w Overall population (n = 59) (n = 66) (n = 64) (n = 64) 1.4 of –54% –33% –70% –70% 1.2 95% CI Eos < 300 cells/µL 1.0 0.62, 1.30 Reproduction1.4 0.8 95% CI –43% –37% –68% –60% ** 0.40, 0.91 1.2 95% CI 0.6 *** 95% CI 0.26, 0.66 *** for 1.0 95% CI 95% CI 0.49, 1.23 0.16, 0.46 0.4 Property0.16, 0.45 0.8 95% CI 95% CI * 0.2 0.29, 0.84 ** Not 0.6 0.25, 0.79 95% CI Adjusted annualized severe 95% CI 0.17, 0.58 0 0.4 0.12, 0.52 Placebo 200 mg 300 mg 200 mg 300 mg exacerbation rate, estimate (95% CI) (n = 158) q4w q4w q2w q2w 0.2 (n = 150) (n = 157) (n = 148) (n = 156) Adjusted annualized severe 0 exacerbation rate, estimate (95% CI) Placebo 200 mg 300 mg 200 mg 300 mg (n = 90) q4w q4w q2w q2w (n = 91) (n = 91) (n = 84) (n = 92) Wenzel, et al. Lancet 2016; 388:31-44. Anti IL‐13 Presenter Lebrikizumabof TralokinumabReproduction for Property Not Lebrikizumab: LAVOLTA I and LAVOLTA II Presenter of Reproduction for Property Not Hanania NA, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016. High‐biomarker group: improved response to Lebrikizumab Presenter of Reproduction for Property Not Hanania NA, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016. Tralokinumab Presenter of Reproduction for Property Not Brightling, E, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; 3:692-701. Tralokinumab: Subset responses based on biomarkers High vs. low Dpp4 High vs. low Periostin High Presenter of Reproduction for Property Not Low Brightling, E, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; 3:692-701. Presenter of Reproduction for Property Not Anti Tezepelumab TSLP Presenter of Reproduction for Property Not Asthma Biomarkers: Moving to endotype • IgE • FeNO • EOS Presenter – Sputum of – Blood Reproduction • Periostin for • Property DPP4 (DipeptidylNot Peptidase 4 / CD26; an adipokine) Other possible immune targets • IL‐33R, ST2 receptor for IL‐33 (GSK3772847) • IL‐17 (brodalumab) • IL‐6 (tocilizumab and others) • TNF (golimumab) Presenter of • M1’ segment of membrane‐expressed IgE (quilizumab) Reproduction for • CRTH2 (fevipripant)Property • TLR9 Not • IL‐25 Future Questions • Are there other biomarkers available for phenotyping and endotyping our patients and helping
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  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011

    Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011

    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.