Biologics in Asthma

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) Anti‐IgE

Presenter Omalizumabof Reproduction for Property Not 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 Benralizumab: Mechanism

Presenter of Reproduction for Property Not 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

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

Presenter Tezepelumabof Reproduction for Property Not 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 guide therapy? Presenter • Is there a role for pharmacogeneticsof in helping to guide our use of biologic agents? Reproduction • Could certain biologicfor agents work better for Property specific racial orNot ethnic groups? More questions …

• Will patients develop resistance to some of these agents, as they do to some of the biologics currently used for autoimmune Presenter conditions? of • Is there a role for the concurrent use of Reproduction several biologics atfor once? • Property What do we doNot with non‐Th2 asthmatics (40‐ 45% of severe asthmatics)? More questions …

• Could biologics change the course of asthma progression? If so, should they be started early, prior to development of severe asthma with remodeling? Presenter • Furthermore, could theyof impact the development of asthmaReproduction … in which case, should they be usedfor in toddlers to help prevent asthma?Property Not • Given their cost in healthcare dollars, who should be given these biologic agents?

Wenzel SE et al. Am J Respir Crit Care Med 1999; 160:1001‐8. Take‐home points

• The introduction of biologics for asthma has been exciting, and the use of these biologics life‐changing for many of our patients. • There are several newerPresenter biologics in the pipeline that hold promiseof for our patients with severe asthma. Reproduction for • Many questionsProperty remain about how best to decide about theirNot use in clinical practice. • There is an unmet need for biologics that can target non‐Th2 asthma. Questions?

Presenter of Reproduction for Property Not