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New Treatment Options for Severe Asthma Modena, Italy March 2011 Eric D. Bateman MD, MBChB, FRCP, DCH Professor of Respiratory Medicine, University of Cape Town Director of University of Cape Town Lung Institute Head, Division of Pulmonology, Cape Town

Outline New Treatment Options for Severe Asthma  Defining the problem  Bronchodilators ICS/LABA and as-needed use Beta2-agonists (ultra-long acting) Anti-muscarinics  Anti-inflammatory drugs PDE4 inhibitors Inhaled corticosteroids  Bronchial Thermoplasty

Severe asthma requiring high intensity treatment ATS / ERS Task Force Asthma Control and Exacerbations Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice Good control on high intensity treatment Poor control despite high intensity treatment Treatment responsive, but with persistent problems e.g. poor adherence, smoking Persistent co- morbidities e.g. GE reflux, obesity Treatment resistant/ refractory asthma “ Severe asthma is defined as the requirement for high intensity treatment after modifiable factors and comorbidites have been appropriately managed” Reddel H, et al, Amer J Resp Crit Care Med 2009;180:59-99

Levels of CONTROL achieved in GOAL Total or Well Controlled* at 52 weeks **p<0.001 vs Fluticasone propionate Salm/FP 500Fluticasone 500 Salm/FP 250Fluticasone 250 Salm/FP 100 Fluticasone n = % of patients CONTROLLED %** 47% Bateman ED et al. Am J Respir Crit Care Med 2004; 170: 836–844 *GOAL definitions of control Previously uncontrolled on moderate doses of ICS Relatively steroid-refractory? Difficult to treat? Relatively steroid-refractory? Difficult to treat?

1.O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129– Rabe KF, et al. Lancet 2006;368:744– Kuna P, et al. Int J Clin Pract 2007;61:725– Bousquet J, et al. Respir Med 2007;101:2437–2446 Patients (% per week) achieving GINA Controlled or Partly Controlled weeks during Bud/Form M&R studies Bud/Form M&R vs High-dose ICS/LABA + SABA 4,5 Bud/Form M&R vs High-dose ICS/LABA + SABA 4,5 Week Controlled and Partly Controlled (%) Bud/Form M&R vs Same-dose ICS/LABA + SABA 1,3 Bud/Form M&R vs Same-dose ICS/LABA + SABA 1,3 Bateman ED et al, JACI % were on Salm/FP 50/500 b.i.d 56%

Same-dose ICS/LABA + SABA vs Bud/Form M&R Same-dose ICS/LABA + SABA vs Bud/Form M&R Exacerbations in week (%) Week Higher-dose ICS/LABA + SABA vs Bud/Form M&R Higher-dose ICS/LABA + SABA vs Bud/Form M&R Week Exacerbations in week (%) Patients (% per week) experiencing exacerbations requiring medical intervention 56 Week Controlled and Partly Controlled (%) Week Controlled and Partly Controlled (%) Bateman ED et al, JACI 2010 Increasing the dose of ICS in the combination inhaler

Ultra-long-acting (once daily) beta2-agonists for asthma Cassola M, et al, Curr Opin Pulm Med 2010; 16: 6 Indacaterol Carmoterol Milveterol GSK BI-1744-CL LAS PF BIG QUESTIONS FDA requirements for safety studies FDA requirements for safety studies Exclusively in combination with ICS Exclusively in combination with ICS What about as-needed use? What about as-needed use? BIG QUESTIONS FDA requirements for safety studies FDA requirements for safety studies Exclusively in combination with ICS Exclusively in combination with ICS What about as-needed use? What about as-needed use? Least squares mean FEV1 (L/min) Indacaterol 600 µg (n = 50) Indacaterol 300 µg (n = 49) Indacaterol 150 µg (n = 47) Formoterol 12 µg (n = 50) Placebo (n = 48) * * * *

Outline New Treatment Options for Severe Asthma  Defining the problem  Bronchodilators ICS/LABA and as-needed use Beta2-agonists (ultra-long acting) Anti-muscarinics  Anti-inflammatory drugs PDE4 inhibitors Inhaled corticosteroids  Bronchial Thermoplasty

Tiotropium as Step-up Treatment in Asthma (TALC) Trial design Peters S, et al, N Engl J Med 2010; 363: 1715 * QVAR BDP 40µg b.i.d. ** Tiotropium HandiHaler ® * QVAR BDP 40µg b.i.d. ** Tiotropium HandiHaler ® * * **

Tiotropium as Step-up Treatment in Asthma TALC Study Demographics (n = 210) Mild- moderate, reversibility and FEV1 >40% pred. Less than 10 pack-years and non-smoking Peters S, et al, N Engl J Med 2010; 363: 1715 Demographic featureValue Male sex (%)33% Atopy (one or more SPT +ve)87% Age (years)42.2 FEV1 (pre-bronchodilator) (L)2.31 FEV1 (post-b.d.)(L)2.62 FEV1 (Pre-b.d.) % predicted71.5 FEV1 reversibility (albuterol)14.9 FEV1 reversibility (ipratropium)12.4 Asthma control days (%)21.2 ACQ (Total score)1.64

Tiotropium as Step-up Treatment in Asthma (TALC) Outcome variables Peters S, et al, N Engl J Med 2010; 363: 1715 Morning PEF Evening PEF Pre-b.d FEV 1 (L) Asthma Control Days (No./14 days) (No./14 days) Asthma Control Days (No./14 days) (No./14 days)

Tiotropium as Step-up Treatment in Asthma Responder analysis: Asthma Control Days Peters S, et al, N Engl J Med 2010; 363: 1715 Percentage patients No response to any Tiotropium Double ICS Salmeterol Tiotropium + Salmeterol Tiotropium + Salmeterol Tiotropium + Salmeterol + Double ICS Tiotropium + Salmeterol + Double ICS 5.4 Salmeterol + Double ICS Salmeterol + Double ICS 7.2 Tiotropium + Double ICS Tiotropium + Double ICS Overall response rates: Tiotropium = 41.5% Salmeterol = 44.5% Double dose ICS = 34.9% Overall response rates: Tiotropium = 41.5% Salmeterol = 44.5% Double dose ICS = 34.9%

Outline New Treatment Options for Severe Asthma  Defining the problem  Bronchodilators ICS/LABA and as-needed use Beta2-agonists (ultra-long acting) Anti-muscarinics  Anti-inflammatory drugs PDE4 inhibitors Inhaled corticosteroids  Bronchial Thermoplasty

Roflumilast in Asthma Run-in period Roflumilast 500 µg/day Double-blindOpen-label extension period weeks 12 weeks40 weeks Placebo Randomization Roflumilast 500 µg/day 250 µg/day 100 µg/day  2 -agonist p.r.n. Roflumilast 250 µg/day Roflumilast 100 µg/day Inclusion criteria: Patients with chronic, stable asthma Patients with chronic, stable asthma Age 15 to 70 years Age 15 to 70 years FEV 1  50% and  85% of predicted value FEV 1  50% and  85% of predicted value Reversibility FEV 1  15% or PEF variability  15% Reversibility FEV 1  15% or PEF variability  15% Inclusion criteria: Patients with chronic, stable asthma Patients with chronic, stable asthma Age 15 to 70 years Age 15 to 70 years FEV 1  50% and  85% of predicted value FEV 1  50% and  85% of predicted value Reversibility FEV 1  15% or PEF variability  15% Reversibility FEV 1  15% or PEF variability  15% Bateman ED, et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol 2006;96:

12-week study Roflumilast 100, 250, 500 µg 40-week study Roflumilast 500 µg Patients (N) Median age in years (range) 40 (16 – 70)42 (17 – 71) Male / Female (%)48 / 5249 / 51 Mean FEV 1 ± SD (L) 100 µg: 2.43 ± µg: 2.38 ± µg: 2.47 ± ± 0.83 FEV 1 ± SD (% predicted) 73 ± 9 85 ± 17 Previous ICS (%) Smokers/Ex-smokers (%)2625 Roflumilast in asthma – a dose-ranging study Bateman ED, et al. Ann Allergy Asthma Immunol 2006;96:

*p < for change vs baseline Roflumilast in asthma: FEV 1 12-week, Dose-Ranging and 40 week extension study Roflumilast ( µg/day ) Change vs baseline (mL) (LSMean) * p = * * 1 LOCF analysis Bateman ED, et al. Ann Allergy Asthma Immunol 2006;96: Change vs baseline (L / min) (LSMean and SEM) Time (weeks) Endpoint 1

M2-111 and M2-112 pooled post hoc analysis Martinez FJ, Calverley PMA, Goehring UM, et al. COPD7 2010; abstract 12. Available at: Roflumilast in COPD: Concurrent with ICS

Pre-specified analysis of exacerbation rate in LABA subgroup Hanania NA, Brose M, Larsson T, et al. Am J Respir Crit Care Med 2010;181:A4435. Abstract. Bateman E, Calverley PMA, Fabbri L, et al. Eur Respir J 2010;36:P4003. Roflumilast in COPD: Concurrent with LABA

Pre-bronchodilator FEV 1 Post-bronchodilator FEV 1 Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Lancet 2009;374: Roflumilast in COPD Concurrent with Tiotropium

Bronchial Thermoplasty for Severe Asthma: AIR 2 Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 Study design: Randomised, double-blind, sham-controlled 2 active:1 control Alair Bronchial Thermoplasty (Asthmatx) BTBTBTBT BTBT BaselineBaseline 4 weeks >3 weeks Follow-upFollow-up Assess3mo.Assess3mo. Assess6mo.Assess6mo.Assess9mo.Assess9mo.Assess12mo.Assess12mo. N = 288 (ITT)

Bronchial Thermoplasty for Severe Asthma Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 Inclusion criteria: Aged 18 – 65 years ICS >1000g/day BDP or equiv. + LABA Plus controllers: LTRA, omalizumab, OCS <10mg/day Stable for 4 weeks AQLQ <6.25 Pre-b.d. FEV1 >60% pred. PD20 M <8mg/ml Symptoms on 2 days in 28 days Non-smoker for at least 12 months and <10 pack-years Exacerbations: <3 hospitalizations, lower respiratory infections and <4 OCS bursts in last year

Bronchial Thermoplasty for Severe Asthma Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 DemographicsBT (n=190)Sham (98) Age (years) Sex (male) PC 20 Methacholine (mg/ml) geometric mean Pre-bronchodilator FEV 1 % predicted ICS (µg/day) (mean) AQLQ (mean) % symptom-free days Other maintenance medications Oral corticosteroids (%) Methylxanthines (%) LTRA (%) Omalizumab (%)1.13.1

Bronchial Thermoplasty for Severe Asthma Primary Endpoint : Change in AQLQ score over 12 months Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 AQLQ Score * months * Posterior probability of superiority = 95% * 6 months3 months 12 months Bronchial Thermoplasty N = 173 Sham N = Average score ▲ ▲ ▲ ▲ ■ ■ ■ ■

Bronchial Thermoplasty for Severe Asthma: Primary Endpoint - % patients achieving change in AQLQ over 12 months Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 Percentage of Subjects Change from baseline in average AQLQ Score * Posterior probability of superiority = 100% Bronchial Thermoplasty Sham < > to < 0.5< 0.5 * Other conclusions: Big placebo effect Side-effects significant in first week Side-effects significant in first week Limited efficacy: no effect on asthma control, rescue use, ACQ, BHR, Limited efficacy: no effect on asthma control, rescue use, ACQ, BHR, Other conclusions: Big placebo effect Side-effects significant in first week Side-effects significant in first week Limited efficacy: no effect on asthma control, rescue use, ACQ, BHR, Limited efficacy: no effect on asthma control, rescue use, ACQ, BHR,

Bronchial Thermoplasty for Severe Asthma Exacerbations and healthcare utilisation over 12 months Castro M, et al, Am J Respir Crit Care Med 2010; 81 : 116 Rate (Events/ subject/ yeear Severe exacerbations * Bronchial Thermoplasty Sham Unscheduled Physician Office Visits EU visits Hospitalizations * Posterior probability of superiority = 95% *

Bronchial Thermoplasty for Severe Asthma Bel E, Am J Respir Crit Care Med 2010; 81 : 116 On the basis of the AIR2 data, does it make sense to offer bronchial thermoplasty to patients with severe asthma? For patients with uncontrolled asthma who have not been submitted to a rigorous treatment protocol, the answer is no. For the remaining patients, the AIR2 results might offer some hope benefit on the quality of life and severe exacerbations. Severe asthma has many phenotypes, and at present we have no clue which phenotype will benefit the most. Long-term clinical and morphological research in various severe- asthma phenotypes is still needed to obtain the required information for clinical decisions

New Treatment Options for Severe Asthma  Severe asthma remains difficult to treat  Several new treatment options are already available  Standardization of definitions and phenotyping will assist the positioning of treatments  More trials testing various combinations are needed  Will the “Asthma cocktail” comprise ICS/LABA (once- daily) and as-needed, anti-muscarinics, combinations of anti-inflammatory drugs, and bronchial thermoplasty??? Summary BIOLOGICALS and TARGETED therapy