Different kinds of asthma, different kinds of therapies Friday 10 th - PowerPoint PPT Presentation

Different kinds of asthma, different kinds of therapies Friday 10 th November 2017 XXXIII Congresso Sezione SIAAIC Toscana Professor Neil Barnes Medical Head Global Respiratory Franchise, GSK Brentford, London Symposium sponsored by GSK Prescribing information is available on request

Disclousures Research Support/P.I. No relevant conflicts of interest to declare Employee I am a full time employee of GSK Consultant No relevant conflicts of interest to declare Major Stockholder I hold stocks and shares in GSK Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

Severe Asthma – Uncontrolled at step 4 once – Co-morbidities – Wrong diagnosis – Adherence/compliance issues

Factors in difficult asthma – Other diseases in association with asthma – Psychological – Adherence/compliance issues – Severe asthma

Asthma diagnosis can be confirmed by excluding other conditions Non-asthmatic conditions misdiagnosed as uncontrolled severe asthma in 12–30% of patients Dysfunctional breathlessness/ Depression vocal cord dysfunction Nasal and sinus complications Endobronchial lesion/foreign body (e.g. cough due to post-nasal (e.g. amyloid, carcinoid, tracheal drip) stricture) Hyperventilation with panic Allergic bronchopulmonary aspergillosis attacks Bronchiolitis obliterans COPD Congestive heart failure Hypereosinophilic syndromes Pulmonary embolus Adverse drug reaction (e.g. ACE inhibitors) Bronchiectasis/cystic fibrosis Chung KF et al. Eur Respir J. 2014;43:343–373.

Prescription filling and health care utilisation Prescription filling <50% ICT n=63 >50% ICT n=119 p value Sex M/F 16/47 53/66 0.02 Admissions in last 25%=3 10%=3 0.02 12 months 5%=2 9%=2 18%=1 16%=1 52%=0 65%=0 Nebuliser 31(49%) 35(29%) 0.01 Total SABA 99 42 0.03 nebules Gamble et al AJRCCM 2009

Baseline FeNO does not identify non-adherence AJRCCM 2012 Dec 1;186(11):1102-8

The utility of fractional exhaled nitric oxide suppression in the identification of non-adherence in difficult asthma Directly observed inhaled steroid therapy AJRCCM 2012 Dec 1;186(11):1102-8

ENFUMOSA study – 12 European centres – Age 17-65 years – Diagnosed <45 years – Well documented asthma – <5 pack years smoking – No other chronic lung disease ERJ 2003;22:470-7

ENFUMOSA study design Well defined asthma Mild to moderate Severe asthma <1000mcg ICS >1200mcg ICS No exacerbations in last year At least one exacerbation in last year ERJ 2003;22:470-7

ENFUMOSA study treatment Controlled Severe Median dose ICS 666 1773 mcg % on long acting inhaled 24.7 95.5 bronchodilator % on 2.5 45.5 theophyllines Oral steroids 0/158 53/163 ERJ 2003;22:470-7

ENFUMOSA study demographics Controlled Controlled Severe vs severe Subjects 158 163 Age years 40.9 42.4 ns Duration of 20.2 20.8 ns asthma Female 1.6:1 4.4:1 p<0.001 :male Atopy IgE 148 108 p<0.05 ERJ 2003;22:470-7

Many factors must be considered and checked to confirm the diagnosis of severe asthma Guideline recommendations for diagnosis of severe asthma Confirm asthma diagnosis Determine if severe Differentiate severe by excluding other asthma is controlled or asthma from milder forms conditions uncontrolled of asthma • Identify/exclude • Check if high-dose ICS • Confirm if severe difficult-to-treat plus a second asthma is controlled asthma controller agent is or uncontrolled while • Treat comorbidities needed to prevent on high-dose therapy affecting asthma attack from becoming (four aspects of control: chronic uncontrolled or if the uncontrolled) rhinosinusitis, GERD, attack remains • Includes asthma that obesity, depression, uncontrolled despite worsens on tapering anxiety, obstructive high-dose therapy of corticosteroids sleep apnoea syndrome • Check inhaler technique/adherence Chung KF et al. Eur Respir J. 2014;43:343–373.

Reduction in oral prednisone requirements in patients with severe asthma 100 * 90 discontinuing prednisone 80 * 70 % patients * p<0.001 60 50 40 30 20 10 0 FP placebo FP 750mcg bd 1000mcg bd Noonan et al, 1995

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

A controlled trial of methotrexate in severe steroid- dependent asthma Shiner et al Lancet 1990

Ciclosporin A in steroid-dependent asthma Lock et al AJRCCM 1996

Immunosuppressive agents evidence of lack of efficacy – Troleandomycin – Colchicine – Hydroxychloroquine – Gamma-globulin

Golimumab tnf-α antagonist in severe asthma Wenzel et al AJRCCM 2009

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

Different asthma phenotypes exist with different pathophysiology Pollution, Microbes Allergens Airway epithelium Goblet cells Macrophages IL-33 IL-17R IL-25 IL-33 TSLP Dendritic cells IL-25 TSLP IL-17A IL-33 Mast CXCL8 Basophil cells NKT GM-CSF cells Naive Th17 T cells cells IL-13 IL-13 ILC2 IgE IL-9 T H 2 IL-4,IL-13 IL-5 IL-5 IL-13 Neutrophils Eosinophils IL-13 B cells Smooth muscle cells Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma Brusselle G, Bracke K . Ann Am Thorac Soc. 2014:11;S322–S328.

Effect of anti-IgE on serum IgE Milgrom et al NEJM 1999

INNOVATE study – 419 patients – FEV1 61% predicted – 28 weeks treatment – 19% reduction in exacerbations NS – 26% reduction when corrected for imbalance of exacerbation history Allergy 2005;60:309

INNOVATE study – FEV1 2.8% predicted better – 0.5 puffs/day less NS – 60.8% vs 47.8% significant 0.5 change in AQLQ Allergy 2005;60:309

Novel therapies – Anti-IL5 Mepolizumab/Resiluzumab/ Benraluzimab – Anti-IL2 Daciluzimab – Anti-IL13 Lebrikizumab – Anti-IL4/13 Dupilimab – Anti TSLP

Anti-IL5 effect on severe exacerbations of asthma 120 109 Placebo 108 Cumulative exacerbation number Anti-IL5 97 100 85 P=0.02 79 80 69 58 60 47 57 55 34 49 40 44 25 40 36 33 14 20 27 21 4 13 7 0 3 1 2 3 4 5 6 7 8 9 10 11 12 Treatment period (months) Haldar et al. NEJM 2009;360:973-84

DREAM: Study design Subjects with severe, uncontrolled asthma with evidence of eosinophilic inflammation Treatment period, N=616 Mepolizumab 750 mg IV every 4 weeks (n=156) Follow-up Mepolizumab 250 mg IV every 4 weeks (n=152) Screening Mepolizumab 75 mg IV every 4 weeks (n=153) R Placebo IV every 4 weeks (n=155) 2 weeks 4 weeks 52 weeks (+/– 5 days) Visits at week 0, week 1, week 4, and at 4-weekly intervals thereafter Visit 2 Visit 17 Visit 1 Visit 16 Randomisation Objective: to evaluate the efficacy, safety and pharmacodynamics of three doses of mepolizumab versus placebo in patients with severe refractory eosinophilic asthma Primary end point: rate of clinically significant asthma exacerbations Pavord ID et al. Lancet . 2012;380:651–659.

DREAM: Key inclusion criteria Background Exacerbation Eosinophilic medication history inflammation • History of ≥ 2 Requirement for ≥ 1 of the Requirement for the following in the previous exacerbations requiring following in the previous 12 months: treatment with systemic 12 months: steroids in previous year • Regular treatment • Blood eosinophil level of ≥ 300/µL with high-dose ICS • Subjects on maintenance (i.e. ≥ 880 µg/day FP OCS required Sputum eosinophils ≥ 3% • ≥ 2-fold increase in the or equivalent) dose of OCS FeNO ≥ 50 ppb • • Controller therapy (e.g. LABA, LTRA) • Deterioration of asthma control following a ≤ 25% • With or without reduction in regular maintenance OCS maintenance inhaled or oral corticosteroids Pavord ID et al . Lancet. 2012; 380(9842):651–659.

The cumulative number of exacerbations over time was reduced with mepolizumab versus placebo 300 Placebo (n=155) Mepolizumab 75 mg (n=153) ~50% Mepolizumab 250 mg (n=152) 250 reduction 750 mg mepolizumab (n=156) significant exacerbations Total number of clinically 200 P <0.001 P <0.001 P <0.001 150 100 50 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time from start of treatment (months) Pavord ID et al. Lancet . 2012;380:651–659.

Blood eosinophil count is a key biomarker of response to mepolizumab therapy DREAM: subjects with markers of eosinophilic disease Blood Eos ≥ 300 cells/µl, or • Sputum Eos ≥ 3%, or • Exhaled nitric oxide concentration ≥ 50 ppb, or • Prompt deterioration of asthma control following a ≤ 25% reduction in • regular maintenance dose of ICS or OCS Modelling of covariates which predict response to mepolizumab • Selection of blood eosinophils as biomarker with best prediction Subgroup Analysis of DREAM data Blood Eos ≥ 150 cells/µl at screening (from modelling data) • Blood Eos ≥ 300 cells/µl in last 12 months (from inclusion criteria) • Katz LE et al. Ann Am Thorac Soc . 2014;11:531–536.