MANAGING ASTHMA..

THE FUTURE THERAPY

Peter J. Barnes FRS, FMedSci

National Heart & Lung Institute, Imperial College London, UK

 RECENT ADVANCES IN ASTHMA THERAPY

• Current therapy and unmet needs

• Single inhaler maintenance and reliever therapy (SMART)

• Anti-inflammatory relievers (AIR)

• New treatments for severe asthma (biologicals)

 ASTHMA TODAY
• Commonest chronic disease in the world
- UK has highest prevalence: ~10% adults, ~20% children (~8 million people)
- Global increase in prevalence (>400 million worldwide)

• Mortality not decreasing (despite effective therapy)

- especially in children and elderly

• Leading cause of hospital admission and time off work

• No cure so long-term therapy needed
• High medical and societal costs
 GINA ASTHMA MANAGEMENT STRATEGY

Severity based on drugs

needed for asthma control
(very
severe)

(severe)

(moderate)
(mild) (mild)
ICS+LABA preferred
for moderate-severe

ICS: inhaled corticosteroid LABA: long-acting inhaled β2-agonist

http://ginasthma.org/2018
 ADDITION OF LABA TO ICS: SEVERE ASTHMA
852 asthmatic patients
95 FACET study FEV ~75% predicted on ~800µg ICS daily
1

OPTIMA STUDY: similar results in mild/moderate asthma

FEV1 (% predicted)

90
Bud 800µg + Formoterol 12µg

85
Bud 200µg + Formoterol 12µg
Bud 800µg
80
Bud 200µg
75 Adding LABA better than 4x dose of ICS
No tolerance over 1 yr
70
-1 0 1 2 3 6 9 12
run-in
Time (months)
Pauwels R et al NEJM 1997 FACET Study O’Byrne P et al AJRCCM 2001
 POOR ASTHMA CONTROL IN THE REAL WORLD
INSPIRE STUDY: Asthma Control Questionnaire (ACQ)
•8000 asthma patients (REALISE Study)
Asthma patients (n=3,415) in 11 countries
••Prescribed
45% uncontrolled
ICS (30%) or ICS + LABA (70%)
• 44% oral steroids in last 12 months
not well • 24% visited emergency department
controlled
• 12% hospitalised
ACQ 0.75-1.5
21%
Price D et al: Primary Care Resp J 2014

• Low adherence to ICS (<20%)

51%
uncontrolled

• Poor inhaler technique ACQ >1.5

28%poor asthma control in the real world

- account for most
well controlled
ACQ <0.75

Partridge M et al: BMC Pulm Med 2006

 POOR ASTHMA CONTROL IN THE REAL WORLD
INSPIRE STUDY: Asthma Control Questionnaire (ACQ)
•8000 asthma patients (REALISE Study)
Asthma patients (n=3,415) in 11 countries
••Prescribed
45% uncontrolled
ICS (30%) or ICS + LABA (70%)
• 44% oral steroids in last 12 months
not well • 24% visited emergency department
controlled
• 12% hospitalised
ACQ 0.75-1.5
21%
Price D et al: Primary Care Resp J 2014

• Low adherence to ICS (<20%)

51%
uncontrolled

• Poor inhaler technique ACQ >1.5

28%poor asthma control in the real world

- account for most
well controlled
ACQ <0.75

Partridge M et al: BMC Pulm Med 2006

 EVOLUTION OF ASTHMA THERAPY
CONVENTIONAL BETTER
No adjustment in Single inhaler:
controller Maintenance & Relief
Combination inhaler
ICS-LABA maintenance 2x daily replaces SABA Trials
SABA reliever prn STAY
SMART = STEAM
Medication Use

Single inhaler Maintenance STEP

And Reliever Therapy COSMOS
SMILE
Other LABAs cannot be used as reliever
COMPASS
Bud-formoterol (Symbicort)
• Salmeterol
Cumulative AHEAD
FP-salmeterol (Seretide) • Vilanterol
side effects
BDP-formoterol (Foster)
• Indacaterol
Maintenance Maintenance
+ prn SABA + prn Bud/form
 SMART REDUCES SEVERE EXACERBATIONS
BUD + SABA Salm-FP + SABA
6 double-blind studies Bud-Form + SABA Bud-Form SMART
(n = 14,351)
Bud-Form + formoterol
*ICS dose 250*
40 1000*
500* 500*
1000*
Exacerbations/100 patients/yr

1000* 1000*
2000*
500*
30

20

10

0
STEAM STEP AHEAD STAY COMPASS SMILE
Chest 2006 CMRO 2004 Resp Med 2004 AJRCCM 2005 IJCP 2007 Lancet 2006
 SMART ↓↓↓ EXACERBATIONS IN REAL LIFE
Exacerbations/100 patients/year 160
145.0 EUROSMART Study: >8,000 patients
140

120 SMART
100

~90% reduction
80

60

40

20
15.9

Previous year Bud/Form

(retrospective data: mainly ICS/LABA +SABA) 2 Puffs BD

Aubier M, et al. Eur Respir J 2010

 GINA ASTHMA MANAGEMENT STRATEGY

(very

~70% of patients (severe)

severe)

(moderate)
(mild) (mild)
SYGMA Studies
BUD-FORM prn ICS+LABA preferred
(vs SABA prn or Budesonide b.d.) for moderate-severe

**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy

http://ginasthma.org/2018 SMART
 SHORT-ACTING β2-AGONISTS (SABA)
salbutamol ,terbutaline
• Most widely used asthma therapy world-wide

• Usually used as rescue therapy (p.r.n.)

However:

• Regular SABA may worsen asthma control

Sears M et al: Lancet 1990

• Regular SABA may increase asthmatic inflammation

Gauvreau G et al: AJRCCM 1997

• Overuse of SABAs is associated with increased asthma mortality

Spitzer W et al: NEJM 1992
 WHY ASTHMA STILL KILLS

ICS LABA
120
120 SABA underuse alone
Total n=195 overuse
Severity
100
100
80
Treatment
80
(inhalers/year)
Deaths Numbers

80

Deaths Numbers
70
60
60

50 60
40

40
20
30
40

20 0
20
10

0
Mild Moderate Severe 0
>12
>12 Rescue >50>50
Rescue <<4
4 ICS <12
<12 ICS LABA
LABA Rx
N=14 N=76 N=61
rescue ICS alone
 BUDESONIDE/SABA RESCUE INHALER
Moderate-severe asthma: adults and children on maintenance ICS (n=3132): 2 yrs

Severe exacerbations
Exacerbations

Salbutamol rescue

Bud 200µg/Salb rescue (↓26%)

Bud 100µg/Salb rescue (↓16%)

Papi A et al: NEJM 2022

 SYGMA STUDIES

SYmbicort Given as-needed in Mild Asthma

 SYGMA1 RESULTS
As-needed terbutaline Budesonide-formoterol
Primary outcome 200/6 µg as required
Mean % of WCAW per patient 0.5 mg
31.1 34.4 (p<0.05)
Severe exacerbations/year
Severe exacerbations/yr

0.25

0.20
0.2
0.2 64% reduction
0.15
0.1 Adherence with
0.10 p<0.01 NS maintenance
inhalers (with 2x daily
0.050 0.09
0.07 reminders) 80%
n=1277 n=1277 n=1282
0.00
Terb prn Bud-form prn Bud b.i.d.
Daily budesonide (57µg) (320µg)
O’Byrne P et al: NEJM 2018 17% of ICS dose
 SYGMA2 RESULTS

0.15 Exacerbation rate Time to first severe exacerbation

Severe exacerbations/yr

Probability of severe exacerbation

N.S. 0.10
As-needed Bud/Form (N=2089)
Budesonide maintenance (N=2087)

0.10
0.10 0.12
0.11
267 μg/day
0.05

0.05
0.05

66 μg/day
(25% ICS dose)
n=2089 n=2087 0.00
0.00 0.00 0 4 8 12 17 20 24 28 34 36 40 44 48 52
Bud-Form
Bud/Formprn Budb.i.d.
prn Bud b.d.
+ SABA Time (weeks)

Adherence 62-64%
Bateman E et al: NEJM 2018
 NOVEL-START STUDY
Mild asthma (n=668) - open-label study:
Salbutamol prn vs bud-form prn vs bud b.d.+ salb prn x 52 weeks
Severe exacerbations

Exhaled nitric oxide (ppb)

(measures eosinophilic inflammation)

Beasley R et al: NEJM 2019

 PRACTICAL: BUD/FORM RESCUE
Open label study: mild-moderate asthma (n=890)
Bud-form 200/6 prn vs budesonide 200 b.d. + terbutaline prn x 1 year
Time to first severe exacerbation
Bud/form prn
P=0.015

Bud b.d. + SABA prn

Hardy J et al. Lancet 2019

 GINA 2021

http://ginasthma.org/2019
 ANTI-INFLAMMATORY RELIEVER (AIR)
ICS-rapid acting β2-agonist should replace SABA as
reliever for mild-severe asthma
• ICS-formoterol
• ICS-SABA
• ICS-formoterol-LAMA (triple)

• More effective for all severities

• Treats increased inflammation
• Addresses poor adherence
• Consistent with patient behaviour
• Cost-effective (less exacerbations)
 LAMA IN POORLY CONTROLLED ASTHMA
Bronchodilatation
(↑FEV1 ~100ml) No improvement in symptoms,
Tiotropium
QoL, asthma control

Placebo
Long-acting muscarinic antagonists
(LAMA)
• Elderly patients
• More fixed obstruction
↓ Acute severe exacerbations • Non-T2
(↓15%) Placebo • Asthma-COPD overlap (ACO)
• 4 week trial of therapy
Tiotropium
• Consider fixed triple inhaler if positive

Kerstjens HAM et al: NEJM 2012

 TRIPLE INHALERS IN ASTHMA
Fixed dose inhaled triple combination inhalers
• BDP + formoterol + glycopyrrolate b.d.(Trimbow)
• Fluticasone furoate + vilanterol + umeclidinium o.d. (Trelegy)
• Budesonide + formoterol + glycopyrrolate b.d. (Breztri)
• Mometasone + indacaterol + glycopyrrolate o.d. (Enerzair)

CAPTAIN Study: Triple vs ICS-LABA

Increase in FEV1 (ml)

Poorly controlled asthma on ICS/LABA (n=2435)
FF/vilanterol vs FF/VI/Umeclidinium od x 24wk

• ↑ FEV1 (~100 ml)

• No ↓ in exacerbations
• No difference in SGRQ (QoL)
FF/VI FF/VI/U 31 FF/VI/U 62
 SEVERE ASTHMA
Severe asthma
- not controlled despite adherence to ICS and good inhaler
technique
~5% of asthma (>50% costs)

Several phenotypes of severe asthma recognised

Inflammatory phenotypes:
• T2 – eosinophilic (~50%)
• Non-T2 - neutrophilic, paucigranulocytic
Anti-eosinophil biological therapies: antibodies
• Anti-IgE (omalizumab): not predictable
• Anti-IL-5 (mepolizumab, reslizumab, benralizumab)
• Anti-IL-4 receptor (dupilumab)
SEVERE ASTHMA: INFLAMMATORY PHENOTYPES
Blood/sputum eosinophils, FeNO, (plasma periostin/DPP4)

T2 immunity Non-T2 immunity (30-50% severe asthma)

Eosinophilic Neutrophilic Paucigranulocytic

Steroid-insensitive
Corticosteroids Steroid-insensitive
Anti-neutrophilic Neurogenic?
Anti-eosinophilic Structural?
Macrolides
Anti-IgE
CXCR2 antagonists
Anti-IL-5 p38 MAPK inhibitors LAMA
Anti-IL-4/13 PDE4 inhibitors LAMA/LABA combo
Anti-TSLP Anti-TNF ICS/LABA.LAMA (triple)
Anti-IL-33 Anti-IL-1
DP2 antagonists Anti-IL-17/23 Bronchial thermoplasty
Masitinib Targeted lung denervation
 ANTI-IgE IN SEVERE ASTHMA
Omalizumab: iv. 2x weekly x 12 weeks
Omalizumab then reduction over 8 weeks
• Severe allergic asthma
Oral steroid reduction Placebo
• Sc injection every 4 weeks 80
Anti-IgE (low dose)
• ToTal IgE 30-700 IU/ml
60 Anti-IgE (high dose)
•

% Patients
↓ exacerbations (~30%)
• ↓ maintenance oral steroids 40

• ↓ seasonal asthma
20

• Treats allergic rhinosinusitis

• Safe (20 yrs use) 0

S
>50% reduction Discontinuing
Milgrom H et al: NEJM 1999
 INTERLEUKIN-5 IN ASTHMA

Priming,
activation
Mast cell

Differentiation
IL-5 (bone marrow)
Th2 cell
IL-5Rα

Survival
ILC2 cell (tissue)
Anti-IL-5 antibody Anti-IL-5Rα antibody
Mepolizumab Benralizumab
(Epithelial cell)
Reslizumab
 EFFECT OF ANTI-IL-5 ON ASTHMA EXACERBATIONS
DREAM Study Patients with severe asthma (GINA4,5) with symptoms
↑ sputum eos on maximal inhaled therapy (3% severe asthma?)
~150 patients/group: 4 weekly injection

Eosinophilic asthma
Frequent exacerbations
No effect on FEV1
No effect on symptoms

~50%↓

Pavord I et al: Lancet 2012

 BENRALIZUMAB IN SEVERE ASTHMA
Exacerbations
IL-5Rα cytotoxic antibody
(depletes tissue and blood eos)

Uncontrolled asthma
(max ICS + LABA)
Effective s.c. every 8 weeks

• ↓ Exacerbations (~50%)
• Blood eosinophils >300/μl
• Little reduction in symptoms
• ↓ Oral steroids
Bleecker ER et al: Lancet 2016
 DUPILUMAB IN ASTHMA
Moderate-severe asthma (n=1902)
Blocks IL-4Rα: IL-4, IL-13 Also very effective in:
Sc every 2 weeks • Atopic dermatitis
FeNO is good biomarker • Chronic rhinosinusitis
• Nasal polyps
Dupilumab sc q2wks
FEV1

Exacerbations ↓ 67%

Castro M et al: NEJM 2018

OTHER BIOLOGICS IN DEVELOPMENT FOR ASTHMA

• Anti-IgE: ligelizumab

• Anti-IL-5: depemokimab: sc every 6 months

• Anti-TSLP: tezepelumab

• Anti-IL-33: etokimab
• itepekimab

• Anti-IL-25: ??

• Anti-IL-17: brodalumab
 Thymic stromal lymphopoietin
(upstream cytokine: alarmin)
ANTI-TSLP
Airway epithelial cells Tezepelumab: 3 doses sc/4w x 52w
Severe asthma (n=436)
(Not controlled on max ICS+LABA)
• ↓ Exacerbations (60-70%)
TSLP • ↑ FEV1
• ↑ AQLQ
• ↓ Blood eosinophils (IL-5)
Immature mDC Mature mDC
• ↓ FeNO (IL-4/13)
CCL17
(TARC)
FeNO
CXCR4
Th2
ILC2

IL-5 IL-4
IL-13
Eosinophil B lymphocyte • Response independent of blood eos
↑ Blood eos ↑ FeNO
Corren J et al: NEJM 2017
 TEZEPELUMAB IN SEVERE ASTHMA
NAVIGATOR Study: (n=1061) tezepelumb (210 mg sc q4w x1yr) in severe uncontrolled asthma

↓ Exacerbations (56%) With blood eos <300 cells/µl

↑ FEV1 ↓ Exacerbations (41%)
↑ AQLQ, ACQ-6
↓ Airway eosinophils
↓ AHR
No oral steroid sparing

Menzies-Gow A et al: NEJM 2021

 ANTI-IL-33 AND ASTHMA
IL-33 (IL-1 family): alarmin
Infection
Damage
Airway epithelial cells
Itepekimab (300 mg sc q4w x 12 wks): n=~70/gp)
↑ asthma control on ICS withdrawal
Th1, ILC1
Anti-IL-33 No different from dupilumab (sc q2wk)
Etokimab No additive effect with dupilumab
IL-33 Itepekimab
↓ blood eos, FeNO
IL-1RacP ST2 Anti-ST2
GSK3772847
ILC2 Neutrophil
Th2

IL-5 IL-4,
IL-13

Eosinophil B lymphocyte

Wechsler ME et al: NEJM 2021

 SMALL MOLECULE INHIBITORS FOR SEVERE ASTHMA

T2 asthma
• DP2 (CRTh2) antagonists: fevipiprant, GB001: failed
• Dexpramipexole: dopamine agonist ↓ blood eos (clinical benefit uncertain)

Non-T2 asthma
• Macrolides: ↓ exacerbations (~40%)
• CXCR2 antagonists: ineffective in neutrophilic asthma
• PDE4 inhibitors:
oral side effects, inhaled ineffective
• p38 MAPK inhibitors:
• JAK inhibitors:
In development
• IRAK4 inhibitors
 CONCLUSIONS
• Asthma poorly controlled in the real world
- poor adherence with ICS, overreliance on SABA

• Anti-inflammatory relievers for all asthmatics:

- ICS-formoterol inhalers as rescue: stop SABA as relievers

• Severe T2 asthma: anti-IL-5, anti-IL-4Rα

- Eliminate need for oral corticosteroids
- New biologics for T2 asthma in development

• Severe non-T2 asthma: new treatments in development