Severe Asthma & Exacerbations: Dawn of a New Era? Christophe von Garnier Department of Pulmonary Medicine Syndromes, Phenotypes & Endotypes Asthma Syndrome Variable symptoms, expiratory airflow limitation, bronchial hyper-reactivity, inflammation Asthma Syndrome Phenotypes Observed characteristics Clinical presentation Trigger Response to therapy Clinical-Biologic Phenotypes Phenotype A Phenotype B Endotypes Functional or physiopathologic mechanisms (link between clinical characteristics and biological pathways) Endotype 1 Endotype 2 Endotype 3 1
Pharmacologic Therapy STEP 5 STEP 4 1. CHOICE CONTROLLER STEP 1 STEP 2 low-dose ICS STEP 3 low-dose ICS/LABA* Interm/high dose ICS/LABA add-on therapy e.g. Anti-IgE Anti IL-5 2. CHOICE CONTROLLER RELIEVER Consider low-dose ICS Leucotrien Receptor Antagonist (LTRA) Low-dose Theophyllin* on-demand short-acting Beta 2 -Agonist (SABA) Interm/high-dose ICS plus Tiotropium# plus low-dose ICS+LTRA High-doseICS Tiotropium# (or + Theoph*) + LTRA plus lowdose (or + Theoph*) OCS On-demand SABA or low-dose ICS/formoterol** www.ginasthma.org Pavord ID et al. Lancet 2018; 391: 350 400 2
Errors with Inhalation Devices n= 4645 Updated for the CRITIKAL patients population from Price et al, Abstract presented IPCRG 2014 DPI = dry powder inhaler; MDI = metered-dose inhaler LAMA worth a try Israel E, Reddel HK. N Engl J Med 2017;377:965-76. 3
Refractory Asthma Incomplete control with GINA Step 4/5 Loss of control when reducing therapy intensity No Is it Asthma? Yes Differential ACO Bronchiectases EGPA ABPA CF EAA VCD Neoplasia No Severe Asthma Complicating Factors? Yes Difficult-to-control Asthma Adapted from Chung KF. Eur Respir J. 2014 43:343-373 Risk factors for exacerbations include: Uncontrolled asthma symptoms Additional risk factors, even if the patient has few symptoms: High SABA use ( 3 canisters/year) Having 1 exacerbation in last 12 months Low FEV 1 ; higher bronchodilator reversibility Incorrect inhaler technique and/or poor adherence Smoking Obesity, chronic rhinosinusitis, pregnancy, blood eosinophilia Elevated FeNOin adults with allergic asthma taking ICS Ever intubated for asthma Risk factors for fixed airflow limitation include: No ICS treatment, smoking, occupational exposure, mucus hypersecretion, blood eosinophilia; pre-term birth, low birth weight Risk factors for medication side-effects include: Frequent oral steroids, high dose/potent ICS, P450 inhibitors www.ginasthma.org 4
Severe Asthma: Biologics for 2018 2021 Anti-IgE Omalizumab Anti-IL5 Mepolizumab Reslizumab Benralizumab Anti-IL4/IL13 Dupilumab Anti-TSLP Tezepelumab Brusselle G Nat Med 2013 5
Brusselle G Nat Med 2013 Omalizumab: Exacerbations Severe exacerbation rate week 28 * 0.6 0.5 0.4 0.3 0.2 0.1 0 0.24 Omalizumab (n=209) p=0.002 0.48 Placebo (n=210) *Severe exacerbation defined as reduction in PEF or FEV 1 to <60% of personal best and requiring treatment with systemic corticosteroids Humbert M et al., Allergy, 2005, Mar;60(3):309-16. 6
Brusselle G Nat Med 2013 Mepolizumab (Anti-IL5) Severe eosinophilic asthma: -frequent exacebations >3.5/yr -ICS > 880 mcg FP -25% OCS -blood eosinophilia > 0.28 G/L -FEV1 <65% Duration 28 weeks Mepo 75mg iv. u. 100mg/Monat sc Annual exacerbation rate: Placebo (n=191): 3.6 1.75 Mepo 75mg iv (n=191): 3.5 0.91 ** Mepo 100mg sc (n=194): 3.8 0.83 ** FEV1: Δ + 146ml (iv), + 136ml (sc) ** AQLQ: Δ 0.42 (iv), 0.44 (sc) ** Ortega HG. N Engl J Med 2014;371:1198-207. 7
Mepolizumab (Anti-IL5) Severe asthma treated with OCS: -frequent exacerbations >2.9/yr -ICS > 880 mcg FP - Median OCS Dose >12mg/d -Blood eosinophilia > 0.23 G/L -FEV1 <60% Duration 20 wks Mepo 100mg/month sc median OCS Dose: 0% PL, -50% Mepo Annual exacerbation rate: Placebo (n=66): 2.9 2.12 Mepo 100mg sc (n=69): 3.3 1.44 * FEV1: Δ + 128ml NS ACQ-5: Δ 0.52 ** Bel EH. N Engl J Med 2014;371:1189-97. Clinical practice: optimisation period Clinical trials: control group Clinical Improvement Specific treatment Placebo effect Hawthorne effect Natural history Time 8
WINDWARD Program in Asthma: Benralizumab Phase 3 Clinical Trials CALIMA 2 Efficacy and safety study of benralizumab in adults and adolescents with asthma, inadequately controlled on mediumto high-dosage ICS-LABA ZONDA 6 Efficacy and safety study of benralizumab to reduce OCS use in patients with uncontrolled asthma on highdosage ICS-LABA and chronic OCS therapy SIROCCO 4 Efficacy and safety study of benralizumab added to high-dosage ICS-LABA in patients with uncontrolled asthma BORA 7 Safety extension study of benralizumab in asthmatic adults and adolescents on ICS-LABA BISE 5 Efficacy and safety study of benralizumab in adults with mild to moderate persistent asthma Six Phase 3 trials in 3068 patients and 798 sites, across 26 countries 1 GREGALE 3 Functionality and reliability of the APFS in an at-home setting and performance of the APFS after use 1. AstraZeneca press release. Published May 17, 2016 2. FitzGerald JM et al. Lancet. 2016; 3. Study NCT02417961. ClinicalTrials.gov website 4. Bleecker ER et al. Lancet. 2016 5. Ferguson GT et al. Lancet Respir Med. 2017 6. Nair P et al. N Engl J Med. 2017 7. Study NCT02258542. ClinicalTrials.gov website. Benralizumab: Cumulative Exacerbations SIROCCO (48 weeks) 1 CALIMA a (56 weeks) 2 1. Bleecker ER et al. Lancet. 2016; 2. FitzGerald JM et al. Lancet. 2016 9
Benralizumab: Summary SIROCCO/CALIMA CALIMA Exacerbations FEV1 Q4W s.c. Q8W s.c. Q4W s.c. Q8W s.c. Eos > 300/μl -36% -28% +125mL +116mL Eos < 300/μl -30% -40% ns ns SIROCCO Eos > 300/μl -45% -51% +106mL +159mL Eos < 300/μl -30% -17% ns ns 1. Bleecker ER et al. Lancet. 2016; 2. FitzGerald JM et al. Lancet. 2016 Benralizumab: OCS sparing (ZONDA) Prednisolone Change Exacerbations Nair P et al. N Engl J Med 2017;376:2448-58. 10
Brusselle G Nat Med 2013 Lebrikizumab (Anti-IL-13): LAVOLTA I & II Hanania NA et al. Lancet Respir Med. 2016 Oct;4(10):781-796. 11
Lebrikizumab (Anti-IL-13): LAVOLTA I & II Hanania NA et al. Lancet Respir Med. 2016 Oct;4(10):781-796. Brusselle G Nat Med 2013 12
Dupilumab (Anti-IL4R): Exacerbations Exacerbations Q4W 200mg Q4W 300mg Q2W 200mg Q2W 300mg All -54% -33% -70% -71% Eos > 300/μl -66% -35% -71% -81% Eos < 300/μl -43% -37% -68% -60% Wenzel SE et al. Lancet. 2016 Jul 2;388(10039):31-44. Brusselle G Nat Med 2013 13
Tezepelumab (Anti-TSLP) Corren J et al. N Engl J Med 2017;377:936-46. Tezepelumab (Anti-TSLP) IgE >100 IU/ml blood Eos >0.14G/L Corren J et al. N Engl J Med 2017;377:936-46. 14
Anti-IgE versus Anti-IL5? Anti-IgE? Anti-IL5 Total IgE Eosinophils Asthma Phenotype early onset late onset Adapted from Lommatzsch M Deutche Med Wochenschrift 2016 Choosing the right Biologic: Role of Co-Morbidities Anti-IgE Omalizumab Chronic rhinosinusitis with nasal polyposis Allergies Urticaria ABPA Maurer M. NEJM 2013 Voskamp AL. JACI 2015 Anti-IL5 Mepolizumab Reslizumab Benralizumab Chronic rhinosinusitis with nasal polyposis Hypereosinophilia EGPA (Churg-Strauss) Roufosse F. JACI 2013 Kim S. JACI 2010 Wechsler ME. NEJM 2017 Anti-IL4/IL13 Dupilumab Chronic rhinosinusitis with nasal polyposis Atopic dermatitis Simpson EL. NEJM 2016 Blauvelt A. Lancet 2017 15
T2 versus non-t2 Asthma T2 nt2 nt2 Haldar P. N Engl J Med. 2009 Mar 5;360(10):973-84. Israel E, Reddel HK. N Engl J Med 2017;377:965-76. 16
Dysbiosis & Neutrophilic Asthma Taylor SL. J Allergy Clin Immunol 2018;141:94-103. Obesity & Neutrophilic Asthma Scott HA et al. Allergy 2016; 71: 1037 1047. 17
Azithromycin & Neutrophilic Asthma Gibson PG. Lancet 2017; 390: 659 68 T2 versus non-t2 Asthma T2 Asthma ICS, OCS Non-T2 Asthma OCS high dose ICS altered airway microbiota systemic inflammation oxidative stress Paucigranulocytic Asthma usually mild asthma severe asthma associated with excessive use of SABA Neutrophilic Asthma usually mild-moderate asthma severe asthma + frequent exacerbations possible Anti-IL17 (Brodalumab) Anti-CXCR2 (AZD 5069) + Azithromycin 18
Phenotype-directed Asthma Therapy Inflammation Allergic Eosinophilic Non-allergic Neutrophilic Pauci -granulocytic Fixed Obstruction Hyperplasia bronchial smooth muscle High-dose ICS Nasal ICS LTRA OCS + Azithromycin Weight loss female obese asthma + Bronchial Thermoplasty? Biologics Immunotherapy Adapted from Rothe T et al. Schweiz Med Forum 2015 Time to review asthma therapy concept? Reliever e.g. SABA, SAMA Controller e.g. ICS, LTRA Collateral efficacy e.g. Biologic & nasal polyps Disease modifier e.g. Biologic, AIT Bateman E ERS 2017 19