severeasthma & exacerbations: dawn ofa new era? · bronchial hyper-reactivity, inflammation...

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Pneumo 24 Glion 27.04.2018

Severe Asthma & Exacerbations: Dawn of a New Era?

Christophe von GarnierDepartment of Pulmonary Medicine


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

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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

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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…

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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

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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

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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

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✗ ✗

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) **

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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 **


Clinical practice: optimisation periodClinical trials: control group

Clin

ical

Impr

ovem

ent

Time

Natural history

Hawthorne effect

Placebo effect

Specific treatment

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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


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

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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


Benralizumab: OCS sparing (ZONDA)

PrednisoloneChange

Exacerbations

Nair P et al. N Engl J Med 2017;376:2448-58.

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✗✗

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

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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


✗

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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.


✗ ✗

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Tezepelumab (Anti-TSLP)

Corren J et al. N Engl J Med 2017;377:936-46.


Tezepelumab (Anti-TSLP)

Corren J et al. N Engl J Med 2017;377:936-46.

IgE >100 IU/mlblood Eos >0.14G/L

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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

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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


Hypereosinophilia

EGPA (Churg-Strauss)

Roufosse F. JACI 2013

Kim S. JACI 2010Wechsler ME. NEJM 2017

Anti-IL4/IL13Dupilumab


Atopic dermatitis Simpson EL. NEJM 2016Blauvelt A. Lancet 2017

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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.

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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

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Pneumo 24 Glion 27.04.2018 Gibson PG. Lancet 2017; 390: 659–68

Azithromycin & Neutrophilic Asthma


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

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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


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

severeasthma & exacerbations: dawn ofa new era? · bronchial hyper-reactivity, inflammation...

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