MICA: Korea-UK PRISM consortium: Establishing Precision Medicine in severe asthma

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

In both UK and Korea, severe asthma is defined as asthma that does not respond adequately to existing treatments including steroids and bronchodilators. It affects up to 5% of asthmatics and represents an important economic burden. In the UK, the economic costs for severe asthma are estimated to be £3-4,000 per patient per year, with these costs dependent on the severity of the asthma and as to whether the patient is using oral corticosteroid therapy. In both UK and Korea, these patients are managed in specialist severe asthma centres which in the UK are commissioned by the Department of Health. Although severe asthma is considered to be a disease with different types (phenotypes), only recently have these patients been divided into groups. With the introduction of new treatments such as antibody treatments to block cytokines such as IL-5, IL-4 and IL13, a high blood eosinophil count is used to choose patients who respond to this treatment. However, we know that this measurement is not an accurate predictor of the response.
A lot of work has been done in the European U-BIOPRED patients with severe asthma to define the different types of asthma by examining and classifying the genes and proteins that are expressed in the subject's blood or sputum cells. Applying this molecular classification has not yet been applied in the severe asthma clinic. We believe that this will bring advantages when used in the clinic because this can tell us for each patient the type of cellular processes or proteins that may be involved in causing the asthma, and ultimately, what type of treatments he or she might need to control the asthma.
Therefore, the aim of this collaborative project between the UK (Professor Chung at Imperial College) and Korea (Professor Kim at University of Ulsan College of Medicine, Seoul) called PRISM is to introduce 'Precision Medicine' (also termed 'personalised medicine') into the treatment of severe asthma. Precision Medicine is the tailoring of treatmen to the individual patient usually by using a diagnostic test based on examining proteins or genes that will guide the most appropriate treatment for this individual person so that the right treatment can be provided to the right patient at the right time.
We propose to do this molecular classification in 400 severe asthma patients who will be observed over a one-year period in several centres specialising in treating patients with severe asthma in both UK and Korea. We wish to see what type of asthma and what diagnostic biomarker measured in the blood or in the exhaled breath that can tell us with great accuracy who will respond well to treatment with the antibody treatments that we have at the moment such as the anti-IL5 or anti-IL5Ra or anti-IL4Ra. For those who cannot have this treatment, we will use the genes and proteins to tell us which type of treatments that might improve their asthma. Therefore, this approach of Precision Medicine will bring newer more effective treatments to subgroups of severe asthma. We foresee that this research will tell us exactly who needs treatment with these antibody treatments, and this will allow patients to take better control of their asthma.
This is a pioneering piece of research because this is the first time that this approach has been taken in the treatment of asthma or any other chronic disease. If we are successful in our objectives, this might pave the way for the establishment of Precision Medicine not only in severe asthma but also in other respiratory and non-respiratory condition, that will provide benefits to a large range of patients suffering from diseases such as severe asthma.

Technical Summary

Severe asthma is a heterogeneous disease where current treatments do not control asthma symptoms and exacerbations. An unmet need is an understanding of the phenotypes and mechanisms. Blood eosinophil count is used to identify suitability for Type-2 (T2)-targeted biologic therapies.
The Korea-UK PRISM consortium will bring precision medicine to severe asthma by (i) validating the molecular phenotypes in UK and Korean cohorts (ii) defining the biomarkers in blood and exhaled breath that predict these molecular phenotypes (iii) determining responders to anti-T2 therapies and (iv) discovering therapeutic targets for T2-low pateints and testing targeted-antibody therapies.
In 400 severe asthma patients, we will determine phenotype according to the biomarker/biomarker signatures obtained from U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) cohort and expression of mechanistic pathways over 3 visits over one year. We will collect blood, exhaled breath condensate and sputum samples for multi-omics platforms, and in Korea, bronchial brushings. We will define the trajectory of molecular phenotypes and pathways using the transcriptomic-associated clusters in sputum transcriptome, and gene set variation analysis. In those receiving T2-targeted biologic therapies, we will find the best molecular signatures that predicting response to individual therapies. We will use model-based mixture models, or hierarchical/k-means clustering and trajectory classification to define phenotypic clusters grouping together patients sharing similar clinical traits.
In studies in Korea, the predictor biomarker/biomarker signature for targeted anti-T2-high therapy will be confirmed and the effect of anti-T2-low antibody therapies in those with high levels of these cytokines/pathways will be examined.
The PRISM Consortium will bring the right treatment to the right patient and newer effective treatments to severe asthma.

Planned Impact

The most important group to benefit from this research will be patients suffering from severe asthma for whom currently there are no effective treatments available. By bringing the right treatment that suits the right patient at the right time using this approach of precision medicine, a significant number of patients with severe asthma will experience improved quality of life and be able to take part in activities that they have missed previously. To explain what precision medicine is and how this may impact on the patient, we have engaged Asthma UK to set up meetings with patients and the public to explain all this.
This research will also impact on the health care provider service because these new treatments which are usually biologic treatments in the from of antibodies are usually expensive and in order for these to become available for use as a treatment, an assessment of the economic health impact will need to be made.
Other groups that will be impacted are the medical and paramedical profession, those taking care of patients with severe asthma. They will need to learn about the new treatments and how these will be administered and in what type of severe asthma patients. Therefore, they will need to be trained in the concept of precision medicine and the use of diagnostic tests to pick up the right patient for the right treatment.
The pharmaceutical companies or biotech companies producing these biologic medicines will be obviously impacted. They will need to perform clinical trials that confirm the beneficial effects of these biologic medicine in specific groups of patients with severe asthma.

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