Ignite New Thinking in COPD: Exploring Type 2 Inflammation

COPD with type 2 inflammation: A spark for deeper COPD understanding

Presented by: Sanofi | Regeneron

Key points from the presentation:

• Low FEV is a significant risk factor for severe COPD exacerbations, which in turn elevate the risk of hospitalization and mortality. Successive severe exacerbations further heighten this risk, exacerbating lung function decline. Additional risk factors include mucus plugging, reduced health status, advancing age, and prolonged oral corticosteroid use.
• Exacerbations may lead to progressive, irreversible lung damage. Following an exacerbation, there's a notable annual decline in both FEV and FVC. More frequent and severe exacerbations are associated with greater lung function deterioration. Approximately a quarter of patients fail to recover lung function within five weeks post-exacerbation, particularly those with GOLD 2, 3, or 4 classifications and frequent exacerbations.
• Each severe exacerbation raises the likelihood of subsequent ones, with the median time between successive severe exacerbations notably shortening. The ninth and tenth exacerbations occur within four months, contrasting with a median time of 5.4 years between initial and subsequent severe exacerbations.
• Chronic airway inflammation in COPD leads to barrier dysfunction, fibrosis, mucus production, and alveolar membrane breakdown. These pathophysiologic changes result in increased permeability, airway obstruction, reduced gas exchange, and hyperinflation. Clinically, this manifests as persistent symptoms, exacerbations, progressive lung function decline, and systemic effects.
• Type 2 inflammation in COPD involves cytokines IL-4, IL-5, and IL-13, contributing to barrier dysfunction, fibrosis, mucus production, and alveolar membrane breakdown. This results in persistent symptoms, exacerbations, progressive lung function decline, and systemic effects, often exacerbated by episodes of acute respiratory symptom worsening (ECOPD).
• Excess mucus leading to airway obstruction significantly increases the risk of death in COPD patients. Participants with mucus plugs had a higher adjusted hazard ratio for mortality compared to those without plugs. The study, adjusted for multiple factors, showed higher mortality rates with increasing mucus plug scores.
• Increased IL-4 expression in COPD patients is strongly associated with frequent exacerbations. Elevated IL-4 levels in bronchoalveolar lavage fluid were linked to the frequent exacerbator phenotype, with both univariate and multivariable analyses confirming this association. This was based on a study of 106 frequent and 106 non-frequent exacerbators.
• Blood eosinophils, a marker of type 2 inflammation, are linked to an increased risk of COPD exacerbations. Counts ≥300 cells/μL help identify patients at higher risk, as shown in studies like ECLIPSE and COPDGene. Higher eosinophil levels correlate with increased incidence rates of exacerbations.
• COPD patients with blood eosinophils ≥300 cells/μL have a higher rate of hospital readmissions within 12 months compared to those with lower eosinophil counts (23.7% vs. 17.1%). This increased risk is consistent across various time points from 30 days to one year.
• Ronald, a 68-year-old ex-smoker with a 40 pack-year history, has non-asthmatic COPD, experiencing breathlessness, cough with mucus, and sleep disturbances. His pulmonary tests reveal pre-BD FEV1 at 1.3L, post-BD FEV1/FVC ratio of 0.5, and 50% predicted post-BD FEV1 with an 8% increase. With two past moderate exacerbations requiring OCS, his eosinophil count aids in identifying potential ICS benefits, alongside consideration of LABA+LAMA therapy due to his FEV1 status.
• Blood eosinophil count guides post-exacerbation management in COPD. For counts <100, LABA+LAMA is recommended; for counts 100–300, LABA+LAMA+ICS is advised. Roflumilast or azithromycin is considered for counts ≥300, especially with FEV1 <50% and chronic bronchitis, but caution is urged due to adverse effects.
• Despite receiving maximal inhaled therapy, a significant proportion of patients experience ongoing moderate-to-severe exacerbations. Approximately 50% of patients on triple-inhaled therapy continued to face such exacerbations, as observed in a Phase III trial analyzing prior exacerbation history.

Conclusion: Exacerbations elevate the risk of subsequent exacerbations, lung function decline, hospitalizations, and mortality in COPD. Type 2 inflammation in COPD heightens the risk of future exacerbations and hospital readmissions. Detecting type 2 inflammation, indicated by high blood eosinophil counts, carries predictive and prognostic significance for COPD patients.

 

 

Session C91 - Emerging strategies in severe asthma in 2024 and beyond

GINA Guidelines 2024

Key points from the presentation:

• Asthma diagnosis is often inaccurate due to non-specific respiratory symptoms and lack of access to quality spirometry, even in high-income countries. Peak expiratory flow (PEF), though less reliable, is a recommended alternative.
• Asthma is frequently managed as a recurrent acute condition, imposing a burden on patients, families, healthcare systems, and the economy. There's a significant risk of asthma-related mortality and adverse effects from oral corticosteroids, even with 4-5 lifetime courses. However, much of the associated morbidity and mortality is preventable.
• Treating asthma with inhaled short-acting beta-agonists (SABA) alone is risky, as even mild cases can result in severe or fatal exacerbations. Overuse of SABA can worsen asthma, increasing airway hyperresponsiveness and allergic reactions. Safer, more effective treatments exist, as regular SABA use leads to poor asthma management and increased mortality.
• FeNO-guided asthma treatment shows no benefit in reducing severe exacerbations or healthcare utilization in pregnant women (BLT study) and no improvement in treatment failure compared to physician-guided or ICS with SABA (BASALT study). An updated meta-analysis is awaited to further evaluate its efficacy.
• FeNO helps diagnose asthma with T2 inflammation but is also elevated in conditions like eosinophilic bronchitis and allergic rhinitis. It is lower in smokers and during bronchoconstriction. FeNO mainly guides treatment decisions in severe asthma, distinguishing between poor adherence and corticosteroid refractory cases, and aids in selecting biologic therapy.
• The goal of asthma management is to optimize long-term outcomes for each patient by ensuring effective symptom control and minimizing risks. This includes having minimal symptoms, no sleep disturbances, unrestricted physical activity, no exacerbations, stable lung function, no need for maintenance oral corticosteroids, and avoiding medication side effects.
• Asthma remission varies by definition and can occur with or without treatment. For children, remission rates differ by age and population, but asthma may recur, indicating remission is not a cure. In adults, remission often involves treatment with biologics or inhaled corticosteroids. Research focuses on new pathways for unmet needs.
• As-needed ICS-formoterol significantly reduces emergency visits and hospitalizations for mild asthma compared to as-needed SABA or daily ICS plus SABA. It is approved in 50 countries and recommended in 32.
• As-needed low-dose ICS-formoterol significantly reduces the risk of severe asthma exacerbations compared to as-needed SABA and is as effective as maintenance low-dose ICS plus as-needed SABA. Symptom control, lung function, and FeNO levels remain stable over 12 months, with patients preferring this treatment approach over daily medication.
• Systematically assessing and adjusting asthma management includes confirming diagnosis, addressing symptoms, risk factors, and comorbidities, optimizing medication use, and providing education. Patient preferences and satisfaction are considered throughout, aiming for personalized and effective care.
• Regular asthma reviews should assess symptom control, exacerbations, lung function, and Type 2 comorbidities. If patients respond well to Type 2-targeted therapy, re-evaluation every 3–6 months is recommended. Gradual reduction or cessation of oral corticosteroids and other add-on medications is advised, followed by potential dose reduction of maintenance ICS-LABA, while ensuring continued asthma management.
• For adults and adolescents aged 12 and above, GINA 2024 emphasizes personalized asthma management through assessment, adjustment, and regular review. Utilizing low-dose maintenance ICS-formoterol as both controller and reliever is preferred, with tailored add-on therapies based on individual needs and phenotypes, promoting symptom control and minimizing exacerbations.
• In GINA Track 1 for adults and adolescents, ICS-formoterol serves as the preferred controller and reliever. This anti-inflammatory reliever regimen, whether used alone or with maintenance therapy, decreases exacerbation risk compared to SABA relievers. It offers a streamlined approach across treatment steps, with referral for expert assessment in severe cases.
• In GINA Track 1, Maintenance and reliever therapy (MART) with low-dose ICS-formoterol significantly reduces severe exacerbations compared to traditional regimens. It surpasses SABA reliever therapy in both eosinophilic and non-eosinophilic asthma, offering superior control across various scenarios, with global approval in approximately 120 countries.
• In GINA Track 1, both budesonide-formoterol and beclometasone-formoterol can be used as anti-inflammatory relievers, available in DPIs and pMDIs. Maximum daily doses are set, with recommendations for usage frequency based on age and treatment step, emphasizing low-dose therapy's effectiveness and safety.
• In GINA Track 2 for adults and adolescents, alternative controller and reliever approaches involve taking ICS whenever SABA is taken, progressing to low-dose maintenance ICS, then ICS-LABA combinations. Before opting for SABA relievers, assess patient adherence to daily ICS treatment. Proper inhaler technique training is crucial, especially if devices differ.

 

Current and Future Biomarkers and Targets in Severe Asthma

Presented by: Celeste Porsbjerg

There has been a paradigm shift in asthma treatment that has evolved from systemic treatment of steroids and adrenergic, to immune-targeted systemic treatments with biologics. With the discovery of biomarkers and an improved understanding of disease pathophysiology, targeted treatments that are individualized are being developed. The advent of personalized medicine has revolutionized the whole approach to the management of asthma, representing the essential basis for future developments. The cornerstones of personalized medicine are biomarkers, and currently three major biomarkers in severe asthma: eosinophils, fractional exhaled nitric oxide (FeNO), and Immunoglobulin E (IgE). 

Session Highlights: 

• Eosinophilic inflammation monitoring in asthma management allows targeted corticosteroids to lower exacerbation frequency and down-titrate corticosteroids.
• Studies have demonstrated that patients with eosinophilic asthma and frequent exacerbation are given targeted biological treatment like mepolizumab they demonstrated lower exacerbation.
• The biologic market for asthma has also seen significant shifts with the development and entry of targeted therapies like anti-IgE, XOLAIR, for allergic asthma in 2005, anti-IL-5s, FASENRA, NUCALA, CINQAIR, for eosinophilic asthma, and anti-IL-4/13, DUPIXENT. 
• The latest entrant is anti-TSLP, TEZSPIRE, in 2022 for all phenotypes with airway responsiveness.
• Airway epithelial cells, in response to different epithelial injuries, secrete alarmins like TSLP, IL-25, and IL-33 that direct T helper cell differentiation toward a Th2 phenotype. Sensitized individuals T helper 2 cells orchestrate allergic inflammation by releasing a typical array of cytokines including IL-4, IL-5, and IL-13. These cytokines and interleukins produce various biomarkers like IgE, FeNO, eosinophils, etc, which correlate to airway hyperresponsiveness, mucus secretion, airway remodeling, etc.
• In severe asthma, elevated T2 biomarkers in combination with exacerbation identify responders to anti-T2 biologics. In severe eosinophilic asthma, epithelial alarmins TSLP and IL-33 increase in response to the virus, while interferon-β decreases.
• Epithelium and mast cells have a role across asthma phenotypes, beyond T2 inflammation. Anti-TSLP, Tezepelumab, targets both epithelial and mast cell-driven inflammation and reduces exacerbation across phenotypes. In PATHWAY and NAVIGATOR trials, it demonstrated notable effects, and there was a decrease in blood eosinophil count, IgE levels, and FeNO levels compared to baseline measurements, significantly. Tezepelumab-treated individuals with asthma exhibited a significant clinical reduction in exacerbation episodes and decreased the need for OCSs.
• Asthma is a heterogeneous condition, where epithelial dysfunction leads to immune hyperreactivity, airway remodeling, elevated T2 biomarkers, reduced lung function, and exacerbation.
• Airway Hyperresponsiveness, due to increased airway reactivity, is a characteristic of exacerbating asthma and is a core feature across phenotypes. It is associated with mast cell infiltration across T2 high and low asthma phenotypes.
• However, there is a significant overlap between these biomarkers, necessitating the identification of additional biomarkers and other novel therapies to develop targeted, personalized treatments for individuals with asthma. To achieve better outcomes one needs to move to “at-risk asthma” from “too late asthma”. This needs early detection and early initiation.
• Biomarkers are being developed to address beyond exacerbations, like address mucus plugging, a key feature of severe asthma associated with loss of lung function. IL-13 drives the secretion of mucin in the airway lumen, while IL-5 promotes eosinophil activation and survival. Mediators from activated eosinophils promote the crosslinking of mucin and mucal gel-stiffening, leading to a plugged airway.
• Immune hyperresponsiveness biomarkers, such as markers of eosinophil cytolysis combined with mucus hypersecretion may form future “AT RISK BIOMARKERS” to guide early biologics treatment initiation.

Conclusion: The advent of personalized medicine has revolutionized the whole approach to the management of asthma, representing the essential basis for future developments. The cornerstones of personalized medicine are the highest precision in diagnosis, individualized prediction of disease evolution, and patient-tailored treatment, to move beyond “TOO LATE ASTHMA”. 

 

Future Topics for Asthma Research - Where Can We Go from Here?

Presented by: Michael E. Wechsler and Praveen Akuthota

Asthma may be a disease with one name. But experts say that unbeknown to most people who have it, it is not just one disease, nor is there a “one-size-fits-all” treatment for it. 

In the last 25 years, the asthma treatment regime has seen a paradigm shift from inhaled steroids and beta-agonists to the development of leukotriene modifiers, and then to precision medicine with the approvals of biologics. Recognition of phenotypes of asthma, and the discovery of simple, clinically accessible biomarkers have improved the disease scenario. Biologic approvals are a good dividing line between the before times and the after times for the management of severe asthma

However asthma is a very dynamic and heterogeneous disease, and biologics reduce exacerbations by approximately 50% only. The are many unaddressed questions even in this biologics regime like why are they not addressing non-type 2 stimuli, and how to determine the best therapy in the absence of comparative head-to-head trials.

GAPS IN THE CURRENT REGIME

• No clear understanding of asthma endotypes dynamism.
• There exist many unanswered questions about non-type 2 asthma, like what is the role of airway microbiome in promoting asthma, or can we identify novel therapies for disease management?
• What about other vulnerable communities, which have a 19% higher attack prevalence rate, 2.5 higher rate of hospitalization, and 16.5% higher death rate? 
• Only 3 biomarkers, (FeNO, IgE, EOS) are readily used. Few are being assessed like DPP$, CRP/IL6, Periostin, Urinart bromotyrosine, etc. but there is a dire need for more.

WHAT THE FUTURE HOLDS

• Multiple developments are happening in the asthma space, and it is not just the development of novel therapies, or therapies with convenient dosing, but also novel diagnostics approaches with the uncovering of novel disease mechanisms.
• Various therapies are under development like 
  • Verekitug: long-acting TSLP receptor antagonist
  • Dexpramipexole: is an oral therapy that improves lung function
  • Itepekimab: reduced exacerbations and is comparable to dupilumab
  • Rilzabrutinib: BTK inhibitor
  • Amlitelimab: Ox-40 ligand
  • Lunsekimig: Anti IL13/TSLP antibody
  • Various JAK inhibitors: in Phase II and others.
• Novel endpoints are also being explored like CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows the design of shorter trials that require fewer patients than studies of severe exacerbations while preserving the ability to show a treatment effect compared with severe exacerbations.

The PrecISE Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States, is conducting Phase II/Proof-of-Concept clinical trials of precision interventions in the population with severe asthma.  It is investigating KIT receptor inhibitor (imatinib), Anti-IL-6 (clazakizumab), GSNO reductase inhibitor genotype (cavosonstat), bacterial extract, etc 

Conclusion: The effectiveness of asthma treatments varies, with current biologics failing to completely eradicate exacerbations, while our understanding of asthma's mechanisms remains rudimentary, lacking specificity in identifying treatment responders—an indispensable aspect of effective care. Nevertheless, the horizon for asthma management holds promise, fueled by burgeoning discoveries elucidating the disease's origins, paving the way for timely interventions. Emerging mechanisms offer novel biomarkers and precise intervention targets, marking a pivotal juncture in the field. This era heralds the advent of medications capable of altering asthma's trajectory, potentially even curing mild cases, and markedly enhancing control and quality of life for the most severe patients.

Can We Achieve Remission and Disease Modification in Severe Asthma Patient

Presented by: David Jackson

Asthma treatment goals currently focus on symptom and exacerbation control rather than remission. Remission is not identical to cure, but is a step closer. In the pre-biologic era, the major criteria for asthma remission was no medication requirement, besides absence of symptoms, or inhaled steroids. Globally there is no consensus on what is asthma remission. 

Several national societies have proposed other definitions of asthma control and remission as treatment targets. In the Japanese guidelines for adult asthma ‘well-controlled’ disease requires the presence of no asthma symptoms, no use of reliever therapy, no limitation of activities, and no exacerbations. The German Respiratory Society guidelines requires a sustained (≥12 months) absence of asthma symptoms and exacerbations, stable lung function, and no need for OCS for the treatment of asthma.  

KEY HIGHLIGHTS

• In the SHAMAL phase IV study, reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab was assessed. Meaningful reductions in ICS therapy while maintaining asthma control was observed. 
• In another remission study, XALOC-1, an international retrospective study of adults with severe asthma and ≥12 months of benralizumab use, clinical remission in patients treated with benralizumab in a real-world was assessed.  After 12 months of follow-up, 71% of patients had no exacerbations, 80% had no maintenance OCS use, and 63% achieved asthma symptom control.
• In a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry who met strict national access criteria for biologics, 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. 
• In some studies, a fall in lung function and rise in FeNO was observed in the subgroup of the patients who stopped regular ICS/LABA, and FeNO predicts accelerated lung function decline. 
• Data from studies also state, that <4% of the people with asthma remain uncontrolled once adherence to inhaled corticosteroids and optimal inhaler technique is achieved.

Conclusion

Defining clinical remission in asthma remains a contentious issue, as existing criteria often overlook extrapulmonary factors contributing to respiratory symptoms. Even when patients meet conventional remission standards, many still experience persistent symptoms due to underlying inflammation driving airway remodeling and lung function decline, detectable through markers like blood eosinophils and FeNO levels. For remission to hold significance, it should not only indicate symptom control but also mitigate future risks, including exacerbations, oral corticosteroid use, and lung function deterioration.

Despite advancements such as biologic therapies, achieving remission is impeded by fundamental challenges such as poor adherence to inhaled corticosteroids, lack of patient education, and underutilization of Type 2 biomarkers. Addressing these barriers is pivotal across all asthma severities to optimize treatment outcomes and enhance patients' quality of life.

 

PATHWAYS in Type 2 Inflammation Global Grant Initiative

Presented by: Klaus F Rabe and Simon Couillard

Asthma and COPD are both heterogeneous respiratory diseases but chronic airway inflammation with recurrent acute exacerbations are common hallmark features of both. Type 2 inflammation has traditionally been associated with asthma, but evidence is emerging that it may also drive COPD severity and exacerbation frequency. Elevated blood eosinophils are adopted as a biomarker for type 2 high disease endotypes and are used to inform clinical decisions around targeted therapy. Eosinophils have a role in both immune homeostasis and immunity. Lung eosinophils are a distinct subset of circulatory eosinophils and there may be differences in eosinophil subtypes between asthma and COPD. 

The precise role of eosinophils in the pathogenesis of COPD and asthma remains unknown and there is a need for a deeper understanding of functional heterogeneity. 

Objective: To determine the difference in eosinophil subsets and functionality between patients with COPD or asthma and healthy controls. Establish and validate scRNAseq and scATACseq analysis pipeline for blood and respiratory samples. 

Methodology: Participants were recruited from the Copenhagen General Population Study, initiated in 2003, which is ongoing and has a Danish cohort. Participants completed a questionnaire and underwent spirometry, biochemical blood analysis, and FeNO testing. Participants were assigned to clinical groups based on self-reported asthma, smoking history, and pre-and post-bronchodilator measurements of FEV1 and FVC. Multiple linear regression analysis was used to determine the association of blood eosinophils.

RESULTS:

• Elevated FeNO levels are associated with accelerated FEV1 decline. 
• Eosinophils participate in both immune homeostasis and immunity
• Individuals with COPD and Asthma had accelerated lung function decline, and there was a relationship between the two type 2 inflammation markers.

Data was also presented from the study phenotyping the responses to systemic corticosteroids in the management of asthma attacks, as responses to systemic corticosteroids in acute asthma vary according to underlying inflammatory phenotype.