Time to Thinking of the Disease-Modifying

Anti-Asthma Drugs for Treatment of Severe Asthma

Siwasak Juthong. M.D.

Respiratory and Respiratory Critical Care Unit, Division of Internal Medicine,
Faculty of Medicine, Prince of Songkla University, Songkhla
Outlines

The Disease-Modifying Anti-Asthma Drugs (DMAAD) for

treatment of asthma

Asthma remission; the future goal for asthma treatment!

Asthma treatment and outcomes

Nolasco, SJ. Pers. Med. 2023,13,1459

 Comparison of asthma treatment concepts in the 20th and 21st centuries

20th century 21st century

Maintenance or intermittent treatment

Systemic corticosteroids Biologics

Short-acting beta-2-agonist monotherapies or cromones Allergen Immunotherapy
Ephedrine or methyxanthines
Inhaled corticosteroids or leukotriene receptor antagonists

Reliever (as needed)

Early 20th century Short-acting beta-2 agonist monotherspies

Scopolamine or epinephrine Inhaled corticosteroids and formoterol

Rescue medications Treatment with Preventive medications

Short-term benefits: Long-tern benefits:

Acute relief of symptoms Treatment concept and aim Disease modification
Remission

Major adverse effects Side-effects Collateral efficiency

One size fits all Application to patients? Individual treatment

Anxiety Patient perspectives Safety

Recurrence symptoms No symptoms
Lommatzsch M. et al. Lancet 2022; 399: 1664–68
 GOALs for the treatment of asthma

Asthma treatment

Symptoms Future Risks

Dyspnea Exacerbation
Exercise limitation Lung function tests
Nocturnal symptom Mortality
Disease modification and asthma remission as therapeutic goals

Asthma guidelines should include a definition for remission as a treatment goal

 Asthma treatments recommended by GINA

Focus on targeting type 2 inflammation (eg, ICS-containing inhalation, biologics,

allergen immunotherapy) are highly effective in reducing asthma exacerbations
and improving asthma control with few adverse effects by preventing
symptoms as well as by reducing future risks

GINA 2023
 The new era of asthma treatment goals

With the advent of effective biologics for the treatment of severe asthma
and a growing number of symptom-free patients on treatment in real life,
this perspective has changed

Definitions of asthma remission independent of the current treatment

status and combined with a long-term view of the partial or complete
remission of signs and symptoms (ie, for at least 12 months) unlike the shorter
periods considered in the concept of asthma control

Lommatzsch M, et al. Disease-modifying anti- asthmatic drugs. Lancet 2022; 399: 1664–68.
 Disease-modifying anti-asthmatic drugs

The management of asthma has changed fundamentally for the past 20 years

Precise assessment and phenotyping are now required to establish

individually targeted treatment with disease-modifying anti-asthmatic drugs
(DMAADs)

DMAADs = ICS-containing inhalations, leukotriene receptor antagonists,

biologics, and allergen immunotherapy

Lommatzsch M. et al. Lancet Respir Med 2023; 11: 573–76

 Disease modification and asthma remission as therapeutic goals

The development and approval of DMAADs has fundamentally changed the

asthma therapy concept from symptom control to symptom prevention

The concept new asthma treatment goal of asthma remission:

- long- term absence of symptoms (good asthma control)
- absence of exacerbations
- stable lung function
- no use of systemic steroids

Marek Lommatzsch. Allergologie select, Vol. 8/2024 (1-5)

 A treat- to-target approach

Used as in rheumatoid arthritis or chronic inflammatory bowel disease

The goal is to achieve asthma remission, through individually tailored

treatment with highly effective drugs with minimal side effects

Requires precise phenotyping, including detailed history taking, pulmonary

function, allergological diagnostics, and measurement of type 2 biomarkers

Marek Lommatzsch. Allergologie select, Vol. 8/2024 (1-5)

 Changes in asthma therapy: symptom prevention as a goal

This paradigm shift was made possible by modern ICS (either ICS, ICS/LABA,
ICS?LABA/LAMA), biologics and modern allergen immunotherapies (AIT)

Analogous to disease-modifying antirheumatic drugs (DMARDs) in

rheumatology)

DMAADs are not only highly effective, but also have few side effects

.
 Asthma remission as a new treatment goal

The remission concepts are based on the remission can also occur during
anti-inflammatory therapy (remission on treatment)

Previously, the concept of asthma remission was limited to spontaneous

remission (especially in pediatrics) or remission after treatment (especially in
allergology, after allergen immunotherapy)
The concept of asthma remission on treatment was previously rejected by
many respiratory physicians;
- not a disease modification (in contrast to all other specialties of internal medicine)
- forms of asthma (especially patients with severe asthma) could ever achieve this goal [1]

Highly effective biologics for the treatment of severe asthma and the
increasing number of permanently symptom-free patients on this therapy
[2], these views have changed

1. Upham JW, James AL. Remission of asthma: The next therapeutic frontier? Pharmacol Ther. 2011; 130: 38-45.
2.. Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. N Engl J Med. 2022; 386: 157- 171.
Changing asthma treatment concepts: from symptom relief to symptom prevention

Treatment with DMAADs aims to prevent asthma symptoms and

exacerbations with minimal treatment-related side-effects, with the ultimate
goal of inducing and maintaining asthma remission

Lommatzsch M. et al. Lancet 2022; 399: 1664–68

 Clinical definitions of asthma remission and disease-modifying anti-asthmatic drugs

Proposed criteria for asthma remission

• Sustained absence of asthma symptoms
• Sustained absence of asthma exacerbations
• Stable lung function
• No need for systemic corticosteroids for the treatment of asthma

Proposed definition of disease-modifying anti-asthmatic drugs

• Any drug class that can potentially achieve the goal of asthma remission

These terms do not necessarily imply biological remission (absence of any airway pathology)

Lommatzsch M. et al. Lancet Respir Med 2023; 11: 573–76 Lommatzsch M. Lancet 2022; 399: 1664–68
The new terminology (DMAAD) might even motivate physicians to
phenotype asthma and to treat asthma to target (analogous to the treatment aim in
rheumatoid arthritis or in IBD) with the currently available spectrum of treatment

options, and to motivate patients to adhere to treatment recommendations

Lommatzsch M. et al. Lancet Respir Med 2023; 11: 573–76

Disease modification and asthma remission as
therapeutic goals
Asthma Remission

Thomas D . Eur Respir J 2022; 60: 2102583

Outcomes in response to biologic treatments in severe asthma
Beasley R, et al. Eur Respir J 2023; 62: 2301844
 Remission on biologics

Early attempts to define clinical remission include composite end points

Biological therapy can raise our ambition towards asthma remission
Lugogo NL, et al. CHEST October 2023, 164: 831-834
Clinical remission in the reduction group 54% at week 48 (ACQ-5 score <1·5)

Jackson D.Lancet 2024; 403: 271–81

In 2023, the concept of remission on treatment has gained support, national societies
have incorporated remission as a treatment goal in asthma guidelines

Criteria for clinical remission of asthma in national guidelines

Lommatzsch M. et al. Lancet Respir Med. 2024 Feb;12(2):96-99.

 Standard treatment steps with standard drugs

Drug D
Severe asthma
Drug C Drug C High treatment burden
Disease control - Many drugs
Phenotyping optional - High doses
Drug B Drug B Drug B - Many adverse effects

Drug A Drug A Drug A Drug A

Step-up treatment

Identification of the right DMAAD(s) for the right patient at the right time
Individual tailored treatment with DMAADs

Identify and treat with Reduction to lowest possible Severe asthma

Disease modification most effective DMAADs number and dose of DMAADs Lowtreatment burden
Phenotyping essential - Few drugs
- Lowest possible doses
Drug B Drug D Drug C - Minimal adverse effects

Drug A Drug C Drug A Drug C

Induction of remission Maintenance of remission

DMAAD=disease-modifying anti-asthmatic drug

Treatment concepts in asthma
Lommatzsch M. et al. Lancet Respir Med. Feb, 2024 Feb;12(2):96-99.
 Treatment concepts in asthma

The new concept of disease modification does not warrant the simple
addition of one drug to another, but the identification of the right DMAAD(s)
for the right patient at the right time.

According to this new concept, phenotyping is an essential prerequisite to

establish individually effective treatment

Lommatzsch M. et al. Lancet Respir Med. 2024 Feb;12(2):96-99.

 The future of asthma therapy

Asthma therapy of the future will consist of 2 phases;

1) An initial phase of remission induction (higher doses, typically a
combination of several DMAADs) and
2) Second phase of remission maintenance (as few DMAADs as possible, in
the lowest possible dose)
There is a need for easy-to-understand, concise guides for general practice

Propose a one-page practical guide for asthma management, titled A2BCD, with 4 components:
A: Dual assessment (A2) of asthma (ie, diagnosis and phenotype, plus asthma control and future risks);
B: Basic measures (B); (eg, education, self- management skills, regular physical activity, and avoidance of asthma triggers);
C: identification and treatment of Comorbidities (C) of asthma (eg, chronic rhinosinusitis, obesity, or sleep apnea);
D: phenotype-specific, individually targeted treatment with DMAADs (D)

Lommatzsch M. et al. Lancet Respir Med 2023; 11: 573–76

A2BCD guide for asthma management

Lommatzsch M. et al. Lancet Respir Med 2023; 11: 573–76

Conclusion

“Disease-modifying anti-asthmatic drugs”, (ICS, ICS/LABA, ICS/LABA/LAMA),

biologics and modern allergen immunotherapies, has fundamentally
changed the asthma therapy concept from symptom control to symptom
prevention
The new asthma treatment goal of asthma remission: long- term
absence of symptoms (good asthma control), absence of exacerbations,
and stable lung function, without the use of systemic steroids for
asthma therapy

A treat- to-target approach is used. The goal is to achieve asthma

remission, through individually tailored treatment with highly effective
drugs with minimal side effects
Thank you for your attention
 Concept of asthma remission

The term remission is well defined in rheumatoid arthritis, Crohn’s disease,

ulcerative colitis, SLE or cancer

Remission in childhood asthma is a common (5% - 69%[1])

Remission in adults with asthma is a relatively new concept and gained attention
Might be possible to induce remission with asthma treatments

Asthma treatment concepts have changed, from short-term symptom control to

long-term symptom prevention, with the achievable goal of disease remission(2)

1. Carpaij OA,. A review on the pathophysiology of asthma remission. Pharmacol Ther 2019;201:8-24.
2. Lommatzsch M, et al. A2BCD: a concise guide for asthma management. Lancet Respir Med 2023; 11: 573–76
 Disease modification and asthma remission as therapeutic goals

The first concept: allergen immunotherapy concept

MITRA study, first to show 1-year treatment with house dust mite (HDM)
sublingual immunotherapy tablet can reduce exacerbations in uncontrolled
asthma and HDM allergy, with an acceptable safety profile (1)

Led to GINA 2021 recommendation that HDM- sublingual immunotherapy

should be evaluated as an additional therapeutic option in the treatment
mild to moderate asthma (2)

1. Virchow JC, et al. Efficacy of a HDM sublingual AIT tablet in adults with allergic asthma: a randomized clinical trial. JAMA 2016; 315: 1715–25.
2. Reddel HK,et al. GINA 2021: executive summary and rationale for key changes. Eur Respir J 2022; 59: 2102730.
 Disease modification and asthma remission as therapeutic goals

Allergen immunotherapy is currently postulated to be a disease modifier,

primarily because clinical benefits and immunological changes last beyond
the time of treatment (ie, the disease remains modified after treatment
discontinuation) (1,2)

1. Pfaar O, et al. One hundred ten years of allergen immunotherapy: a broad look into the future. J Allergy Clin Immunol Pract 2021; 9: 1791–803.
2. Marogna M, et al. Long-lasting effects of sublingual immunotherapy according to its duration: a 15-year prospective study. J Allergy Clin Immunol 2010;
 Disease modification and asthma remission as therapeutic goals

The second concept: the rheumatoid arthritis concept

The European League Against Rheumatism defines a large group of modern

anti-inflammatory drugs against rheumatoid arthritis as disease modifiers or
disease-modifying anti-rheumatic drugs (DMARDs) (1)

Linked to idea of rheumatoid arthritis remission, defined as a very low

disease activity (the patient must satisfy all of the following: tender joint count ≤1, swollen joint count ≤1, C-reactive
protein ≤1 mg/dl, and patient global assessment ≤1, on a 0–10 scale) during treatment with DMARDs (2)

1. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79: 685–99.
2. Felson DT, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011; 70: 404–13.
Today, effective, safe, phenotype-specific immunomodulatory drugs aimed
at preventing symptoms and exacerbations by targeting the underlying
inflammatory cascade, with the advantage of improving control of co-
existing co-morbidities

Drugs do not only successfully modulate inflammation, but can improve the
function of structural cells, such as epithelial cells, smooth muscle cells,
fibroblasts, and nerves, and consequently reduce airway remodelling

Lommatzsch M. Lancet 2022; 399: 1664–68

The choice of inhaled therapies has become more and more individualize

ICS/LABA (LAMA)
fixed combination Application schemes
inhaler maintenance therapy
or inhalation on an as- needed basis

ICS molecules,
ICS doses Inhaled Devices
Asthma

Lommatzsch M. Lancet 2022; 399: 1664–68

 Types and measures of asthma remission
Type Criteria
Clinical remission No symptoms
No exacerbations
Optimisation of lung function
Complete remission Clinical remission plus
normalisation of underlying
pathology
Both clinical and complete remission can be achieved either on treatment or off treatment.
12 months or longer without symptoms
Assessments
Sustained absence of significant asthma symptoms established
using a validated instrument (e.g. ACQ score ⩽1 or ACT score
⩾20); the use of relievers is not permitted during the remission
period
The use of systemic corticosteroids for exacerbation treatment
is not permitted during the remission period; hospitalisation or
emergency department visit or unscheduled doctor visit for
asthma exacerbation management are also not permitted
during the remission period
Example: post-bronchodilator FEV1 ⩾80% predicted
No evidence of current inflammation established using either blood
eosinophil count (<300 cells·μL−1), sputum eosinophil count (<3%) or
FENO (<40 ppb); other measures of underlying pathology may
include a negative bronchial hyperresponsiveness test (e.g.
histamine or methacholine provocation tests) or degree of
subepithelial fibrosis (subepithelial thickness)
Thomas D . Eur Respir J 2022; 60: 2102583
 Types and measures of asthma remission
Type Criteria
Clinical remission No symptoms
No exacerbations
Optimisation of lung function
Complete remission Clinical remission plus
normalisation of underlying
pathology
Both clinical and complete remission can be achieved either on treatment or off treatment.
12 months or longer without symptoms
Assessments
Sustained absence of significant asthma symptoms established
using a validated instrument (e.g. ACQ score ⩽1 or ACT score
⩾20); the use of relievers is not permitted during the remission
period
The use of systemic corticosteroids for exacerbation treatment
is not permitted during the remission period; hospitalisation or
emergency department visit or unscheduled doctor visit for
asthma exacerbation management are also not permitted
during the remission period
Example: post-bronchodilator FEV1 ⩾80% predicted
No evidence of current inflammation established using either blood
eosinophil count (<300 cells·μL−1), sputum eosinophil count (<3%) or
FENO (<40 ppb); other measures of underlying pathology may
include a negative bronchial hyperresponsiveness test (e.g.
histamine or methacholine provocation tests) or degree of
subepithelial fibrosis (subepithelial thickness)
Thomas D . Eur Respir J 2022; 60: 2102583
 32.1% of those initiating biologics achieved remission
9.5% of patients not receiving biologics met remission criteria

The biologic super-response rate was 61.4% (without the lung function criterion),
superresponse rate = 34.8% not receiving biologics

3. Milger K, Suhling H, Skowasch D, Holtdirk A, Kneidinger N, Behr J, et al. Response to biologics and clinical remission in the adult GAN severe asthma registry
cohort. Allergy Clin Immunol Pract 2023;11:2701-12.
The general concept of treatment recommendations is phenotype-specific,
anti-inflammatory DMAAD therapy, moving towards clever “fire prevention”
and away from constant “fire extinguishing”
Varricchi G, et al. Allergy. 2022;77:3538–3552
Time to change the paradigm of treatment for
patients with severe asthma who have
frequent severe exacerbations, multiple OCS
bursts and severe symptom burden, to the
treatment goals from asthma control to
asthma remission by biologics