1
Pneumo 24 Glion 27.04.2018
Severe Asthma & Exacerbations: Dawn of a New Era?
Christophe von GarnierDepartment of Pulmonary Medicine
Pneumo 24 Glion 27.04.2018
Syndromes, Phenotypes & Endotypes
Asthma SyndromeVariable symptoms, expiratory airflow limitation, bronchial hyper-reactivity, inflammation
Asthma Syndrome
PhenotypesObserved characteristics• Clinical presentation• Trigger• Response to therapy
Phenotype A Phenotype B
EndotypesFunctional or physiopathologic mechanisms(link between clinical characteristics and biological pathways)
Endotype1
Endotype2
Endotype3
Clinical-Biologic Phenotypes
2
Pneumo 24 Glion 27.04.2018
Pharmacologic Therapy
1. CHOICECONTROLLER
2. CHOICECONTROLLER
RELIEVER
STEP 1 STEP 2 STEP 3
STEP 4
STEP 5
low-dose ICS
Consider low-dose ICS
Leucotrien Receptor Antagonist (LTRA)Low-dose Theophyllin*
Interm/high-dose ICSlow-dose ICS+LTRA
(or + Theoph*)
on-demand short-acting Beta2-Agonist (SABA) On-demand SABA or low-dose ICS/formoterol**
low-doseICS/LABA*
Interm/highdose
ICS/LABA
add-ontherapy
e.g.Anti-IgEAnti IL-5
plus Tiotropium#High-doseICS+ LTRA (or + Theoph*)
plus Tiotropium#plus low-dose OCS
www.ginasthma.org
Pneumo 24 Glion 27.04.2018 Pavord ID et al. Lancet 2018; 391: 350–400
3
Pneumo 24 Glion 27.04.2018
Errors with Inhalation Devices
Updated for the CRITIKAL patients population from Price et al, Abstract presented IPCRG 2014DPI = dry powder inhaler; MDI = metered-dose inhaler
n= 4645
Pneumo 24 Glion 27.04.2018 Israel E, Reddel HK. N Engl J Med 2017;377:965-76.
LAMA worth a try…
4
Pneumo 24 Glion 27.04.2018 Adapted from Chung KF. Eur Respir J. 2014 43:343-373
Refractory Asthma• Incomplete control with GINA Step 4/5• Loss of control when reducing therapy intensity
Is it Asthma?
Differential• ACO• Bronchiectases• EGPA• ABPA• CF• EAA• VCD• Neoplasia…
No
Complicating Factors?
Yes
Severe Asthma
No
Difficult-to-control Asthma
Yes
Pneumo 24 Glion 27.04.2018 www.ginasthma.org
Risk factors for exacerbations include:• Uncontrolled asthma symptomsAdditional risk factors, even if the patient has few symptoms:• High SABA use (≥3 canisters/year)• Having ≥1 exacerbation in last 12 months• Low FEV1; higher bronchodilator reversibility• Incorrect inhaler technique and/or poor adherence• Smoking• Obesity, chronic rhinosinusitis, pregnancy, blood eosinophilia• Elevated FeNO in 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
5
Pneumo 24 Glion 27.04.2018
Severe Asthma:Biologics for 2018
Anti-IgEOmalizumab
Anti-IL5MepolizumabReslizumabBenralizumab
Æ 2021
Anti-IL4/IL13Dupilumab
Anti-TSLPTezepelumab
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
6
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
✗
Pneumo 24 Glion 27.04.2018
Omalizumab: Exacerbations
Humbert M et al., Allergy, 2005, Mar;60(3):309-16.
0.24
0.48
Omalizumab(n=209)
Placebo(n=210)
0.6
0.5
0.4
0.3
0.2
0.1
0
p=0.002
Seve
re e
xace
rbat
ion
rate
wee
k 28
*
*Severe exacerbation defined as reduction in PEF or FEV1 to <60% of personal best and requiring treatment with systemic corticosteroids
7
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
✗ ✗
Pneumo 24 Glion 27.04.2018 Ortega HG. N Engl J Med 2014;371:1198-207.
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 weeksMepo 75mg iv. u. 100mg/Monat sc
Annual exacerbation rate:Placebo (n=191): 3.6 Æ 1.75Mepo 75mg iv (n=191): 3.5 Æ 0.91 **Mepo 100mg sc (n=194): 3.8 Æ 0.83 **
FEV1: Δ + 146ml (iv), + 136ml (sc) **AQLQ: Δ 0.42 (iv), 0.44 (sc) **
8
Pneumo 24 Glion 27.04.2018 Bel EH. N Engl J Med 2014;371:1189-97.
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
Ð median OCS Dose: 0% PL, -50% Mepo
Annual exacerbation rate:Placebo (n=66): 2.9 Æ 2.12Mepo 100mg sc (n=69): 3.3 Æ 1.44 *
FEV1: Δ + 128ml NS
ACQ-5: Δ 0.52 **
Pneumo 24 Glion 27.04.2018
Clinical practice: optimisation periodClinical trials: control group
Clin
ical
Impr
ovem
ent
Time
Natural history
Hawthorne effect
Placebo effect
Specific treatment
9
Pneumo 24 Glion 27.04.2018
WINDWARD Program in Asthma: Benralizumab Phase 3 Clinical Trials
Six Phase 3 trials in 3068 patients and 798 sites, across 26 countries1
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. 20165. Ferguson GT et al. Lancet Respir Med. 2017 6. Nair P et al. N Engl J Med. 20177. Study NCT02258542. ClinicalTrials.gov website.
CALIMA2
Efficacy and safety study of benralizumab in adults and adolescents with asthma,
inadequately controlled on medium-to high-dosage ICS-LABA
SIROCCO4
Efficacy and safety study of benralizumab added to high-dosage
ICS-LABA in patients with uncontrolled asthma
ZONDA6
Efficacy and safety study of benralizumab to
reduce OCS use in patients with uncontrolled asthma on high-
dosage ICS-LABA and chronic OCS therapy
BORA7
Safety extension study of benralizumab in asthmatic adults
and adolescents on ICS-LABA
GREGALE3
Functionality and reliability of the APFS in an at-home setting and
performance of the APFS after use
BISE5
Efficacy and safety study of benralizumab in adults with mild to
moderate persistent asthma
Pneumo 24 Glion 27.04.2018
Benralizumab: Cumulative Exacerbations
1. Bleecker ER et al. Lancet. 2016; 2. FitzGerald JM et al. Lancet. 2016
SIROCCO (48 weeks)1
CALIMAa (56 weeks)2
10
Pneumo 24 Glion 27.04.2018
Exacerbations FEV1Q4W s.c. Q8W s.c. Q4W s.c. Q8W s.c.
CALIMAEos > 300/μl -36% -28% +125mL +116mL
Eos < 300/μl -30% -40% ns ns
SIROCCOEos > 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: Summary SIROCCO/CALIMA
Pneumo 24 Glion 27.04.2018
Benralizumab: OCS sparing (ZONDA)
PrednisoloneChange
Exacerbations
Nair P et al. N Engl J Med 2017;376:2448-58.
11
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
✗ ✗
✗✗
Pneumo 24 Glion 27.04.2018 Hanania NA et al. Lancet Respir Med. 2016 Oct;4(10):781-796.
Lebrikizumab (Anti-IL-13): LAVOLTA I & II
12
Pneumo 24 Glion 27.04.2018 Hanania NA et al. Lancet Respir Med. 2016 Oct;4(10):781-796.
Lebrikizumab (Anti-IL-13): LAVOLTA I & II
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
✗
13
Pneumo 24 Glion 27.04.2018
ExacerbationsQ4W 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%
Dupilumab (Anti-IL4R): Exacerbations
Wenzel SE et al. Lancet. 2016 Jul 2;388(10039):31-44.
Pneumo 24 Glion 27.04.2018 Brusselle G Nat Med 2013
✗ ✗
14
Pneumo 24 Glion 27.04.2018
Tezepelumab (Anti-TSLP)
Corren J et al. N Engl J Med 2017;377:936-46.
Pneumo 24 Glion 27.04.2018
Tezepelumab (Anti-TSLP)
Corren J et al. N Engl J Med 2017;377:936-46.
IgE >100 IU/mlblood Eos >0.14G/L
15
Pneumo 24 Glion 27.04.2018
Anti-IgE versus Anti-IL5?
Anti-IgEAnti-IL5
Total IgE Ï Ð
Eosinophils Ï ÏÏ
Asthma Phenotype
“early onset” “late onset”
Adapted from Lommatzsch M Deutche Med Wochenschrift 2016
?
Pneumo 24 Glion 27.04.2018
Choosing the right Biologic: Role of Co-Morbidities
Anti-IgEOmalizumab
Chronic rhinosinusitis with nasal polyposis
Allergies Urticaria ABPA Maurer M. NEJM 2013Voskamp AL. JACI 2015
Anti-IL5MepolizumabReslizumabBenralizumab
Chronic rhinosinusitis with nasal polyposis
Hypereosinophilia
EGPA (Churg-Strauss)
Roufosse F. JACI 2013
Kim S. JACI 2010Wechsler ME. NEJM 2017
Anti-IL4/IL13Dupilumab
Chronic rhinosinusitis with nasal polyposis
Atopic dermatitis Simpson EL. NEJM 2016Blauvelt A. Lancet 2017
16
Pneumo 24 Glion 27.04.2018 Haldar P. N Engl J Med. 2009 Mar 5;360(10):973-84.
T2 versus non-T2 Asthma
T2
nT2nT2
Pneumo 24 Glion 27.04.2018 Israel E, Reddel HK. N Engl J Med 2017;377:965-76.
17
Pneumo 24 Glion 27.04.2018 Taylor SL . J Allergy Clin Immunol 2018;141:94-103.
Dysbiosis & Neutrophilic Asthma
Pneumo 24 Glion 27.04.2018 Scott HA et al. Allergy 2016; 71: 1037–1047.
Obesity & Neutrophilic Asthma
18
Pneumo 24 Glion 27.04.2018 Gibson PG. Lancet 2017; 390: 659–68
Azithromycin & Neutrophilic Asthma
Pneumo 24 Glion 27.04.2018
T2 versus non-T2 AsthmaT2 Asthma
Non-T2 Asthma
ICS, OCS
Paucigranulocytic Asthma• usually mild asthma• severe asthma associated
with excessive use of SABA
Neutrophilic Asthma• usually mild-moderate asthma• severe asthma + frequent
exacerbations possible
• OCS• high dose ICS• altered airway microbiota• systemic inflammation• oxidative stress
− Anti-IL17 (Brodalumab)− Anti-CXCR2 (AZD 5069)+ Azithromycin
19
Pneumo 24 Glion 27.04.2018
Phenotype-directed Asthma TherapyInflammation
Adapted from Rothe T et al. Schweiz Med Forum 2015
Eosinophilic Fixed ObstructionHyperplasia bronchial smooth muscle
Neutrophilic Pauci-granulocytic
Allergic Non-allergic
High-dose ICSNasal ICSLTRAOCS
+AzithromycinWeight loss female obese asthma
+BronchialThermoplasty?
Biologics
Immunotherapy
Pneumo 24 Glion 27.04.2018
Time to review asthma therapy concept?
Controllere.g. ICS, LTRA
Disease modifiere.g. Biologic, AIT
Collateral efficacye.g. Biologic
& nasal polyps
Relievere.g. SABA, SAMA
Bateman E ERS 2017