“Severe Asthma Data in SARP” presented by Dr. Mario Castro
As part of our ongoing seminar series, the Centre of Excellence in Severe Asthma hosted Dr. Mario Castro, for a webinar on “Severe Asthma Data in SARP” on 19 June, 2018.
Please note: Unpublished data slides have been redacted from the webinar recording at the request of Dr. Castro.
Presentation Summary:
Dr. Castro presents findings from the Severe Asthma Research Program (SARP), providing insights into severe asthma disease phenotypes and approaches for targeted therapy.
The SARP network links 7 asthma clinical university centres and 1 data coordinating centre in the USA, sponsored by the National Institutes of Health (NIH). The SARP network has been operational for 2 decades and the current 3rd phase (SARP III) has enrolled over 700 participants. The SARP network’s mission is to “improve the understanding of severe asthma in order to develop better treatments.”
Dr. Castro highlights the use of imaging technologies to better understand the lung changes that occur in severe asthma. His findings identify subgroups of patients with specific changes in the lung. The hope is that identification of these subgroups will inform the use of targeted therapies.
Dr. Castro also presents data on the effects of dupilumab treatment. Dupilumab is a monoclonal antibody that targets IL-4 receptor alpha (anti-IL-4Ra). Recent clinical trials published in the New England Journal of Medicine showed that dupilumab treatment improves patient outcomes.
Key Points:
- The SARP network has produced over 250 publications over 2 decades, with over 30 from the imaging group led by Dr. Castro
- There is a major unmet need for patients with severe persistent asthma, particularly for patients with non-eosinophilic, mucus and chronic airflow obstruction phenotypes
- Targeted treatment approaches with minimal side effects are required for severe asthma, as part of a precision medicine approach
- SARP provides insights into the stability and evolution of severe asthma phenotypes, demonstrating that phenotype can change over time
- Increased epithelial thickness, lamina reticularis thickness, smooth muscle actin and cellular proliferation and apoptosis are observed in tissue samples from severe asthma patients (Cohen 2007 AJRCCM)
- The cytokine IL-13 contributes to airway remodelling, increasing goblet cell numbers and reducing ciliated epithelial cell numbers
- Imaging studies reveal persistent mucus plugs in over 50% of patients with severe asthma, representing a potential “mucus phenotype” (Dunican 2018 J Clin Invest)
- The mucus phenotype is associated with reduced lung function, increased sputum eosinophil numbers, increased IL-13 levels and abnormal mucus gene expression
- Dupilumab (anti-IL-4Ra antibody) blocks IL-4 and IL-13 signaling
- In clinical trials, dupilumab treatment reduced severe exacerbations rates and improved lung function (Castro 2018 NEJM)
- Dupilumab treatment was effective in patients across a range of baseline eosinophil counts and fractional exhaled nitric oxide (FeNO) levels (although it is less effective in patients with FeNO <25ppb)
- Dupilumab also reduced exacerbation rate, oral corticosteroid use and improved lung function and asthma control in a 2nd clinical trial (Rabe 2018 NEJM)
- Side effects observed following dupilumab treatment included eosinophilia and injection site reactions
- Targeted treatment options for patients with chronic airflow obstruction may include anti-IL-13 and bronchial thermoplasty
- Increased smooth muscle thickness is observed in the lungs of a subset of patients with severe asthma, assessed in biopsy tissue and using non-invasive high-resolution computed tomography (HRCT) imaging (Aysola 2008 CHEST)
- Preliminary findings from lung imaging studies reveal differences in lung structure between people with asthma, which cluster patients into different subsets that may represent novel disease phenotypes (Choi 2017 JACI)
- Patients with severe asthma have reduced numbers of small vessels in the lung, which was associated with a number of disease factors (Ash 2018 AJRCCM)
- Bronchial thermoplasty is a treatment approach that applies thermal energy to the airway wall
- Following bronchial thermoplasty treatment, decreased airway smooth muscle correlated with improved clinical outcomes (Pretolani 2017 JACI)
About Dr. Mario Castro:
Dr. Castro is the Alan A. and Edith L. Wolff Professor of Pulmonary and Critical Care Medicine at the Washington University School of Medicine (St Louis, MO).
Dr Castro’s specialties include asthma and related allergic disease, COPD, emphysema, chronic bronchitis, chronic cough and unexplained shortness of breath. Dr Castro is active in research and is working under several grants from the National Institutes of Health (NIH) regarding the causes of asthma, especially severe asthma, as part of the Severe Asthma Research Program (SARP).
He is the Principal Investigator of several networks sponsored by the NIH, Patient-Centered Outcomes Research Institute and American Lung Association, evaluating the management and treatment of asthma and airway diseases. He has been a Member of the Scientific Advisory Board at Therabron Therapeutics, Inc. since May 19 2016. He is the recipient of numerous awards and is author or co-author of more than 200 peer reviewed articles.
Dr. Mario Castro’s travel was supported by AstraZeneca
