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= The UK Refractory Asthma Stratification Programme (RASP-UK) =

The RASP-UK Consortium is a partnership of clinical and academic excellence from UK Universities and NHS Severe Asthma Centres, patient representatives and the pharmaceutical industry. The primary focus of this ongoing clinical research programme into asthma is to target effectively corticosteroid treatments and to understand why some patients do not respond to these therapies. Industry partners developing new treatments for severe asthma partner with respiratory physicians and centres of excellence, patients to rigorously test hypothesis to lead to novel asthma ‘biomarkers’ that will help them predict response to their new therapies.

Background
Asthma affects an estimated 300 million people worldwide with a population prevalence of approximately 15% in the UK [1]. The WHO has estimated UK disability adjusted life-years per 100,000 population for asthma to be greater than diabetes and breast cancer [2]. In subjects with mild disease, currently available treatments work well but, in 10–20% of patients with asthma, their condition is difficult to control [3, 4]. These patients consume 50–60% of the healthcare costs attributed to asthma [5, 6] and cost approximately five-times more than patients with mild stable disease [7]. This high morbidity and disproportionate use of healthcare resources reflects the considerable un-met need in this patient group, and their significance for healthcare providers.

History
The concept behind the RASP initiative, to test a novel strategy to stratify or categorise severe asthma – identifying patients who don’t respond to steroid treatment (MOU1)  - with the aim of improving clinical management and accelerating the development of new treatments, emerged from discussions held at Queen’s University Belfast held in 2012. In November 2013, Asthma UK hosted a consensus workshop to bring together leading researchers, industry and pharmaceutical partners and patients to design a research programme which would address one of the biggest unmet needs in asthma care – the fact that some people with the most severe asthma don’t respond to steroids, leaving them with very few treatment options and having a huge impact on their quality of life.

In 2014 the project was awarded funding of £4.8 million from the Medical Research Council (MRC: Grant (MOU2), matched by a further £4.8 million from pharmaceutical and industry partners, representing a huge investment in asthma research with the aim of changing the way patients, doctors and health care decision makers understand and treat severe asthma. Subsequent to the award additional partners have brought novel research aspects and funding to the programme.

Work-strand 1
Asthma has been traditionally ‘stratified’ on the basis of response to ‘step-wise’ incremental treatment, with inhaled corticosteroid (ICS) therapy forming the cornerstone of this approach. However, more recently, asthma has been stratified on the basis of inflammatory phenotype to better understand disease heterogeneity with a view to developing biomarkers of therapeutic response and for better targeting of both new and existing treatments. Using sputum analysis [8], and more recently whole genome expression profiling [9], it is clear that even in mild steroid-naïve asthma approximately 50% of patients do not have a typical type 2 (T2)-driven eosinophilic inflammation, and are called ‘T2-low asthma’ patients. Perhaps more significantly, on the basis of the normal diagnostic criteria for asthma, this T2-low group is indistinguishable from the typical ‘T2-high’/eosinophilic group. However, in the context of therapeutic response, the T2-low patients have a minimal response to ICS therapy [8, 9]. In severe disease, the T2-low profile is also prevalent [10, 11], and in case series of difficult-to-treat patients with asthma there is substantial evidence that inappropriate escalation of corticosteroid treatment is frequent, with significant morbidity due to systemic corticosteroid exposure [12–14]. In a follow-up analysis of the largest “real-world” refractory asthma cohort to date in the British Thoracic Society Difficult Asthma Network in the UK [15] the most common therapeutic intervention in specialist centres was the addition of systemic corticosteroid treatment, with approximately 60% ending up on oral corticosteroids [16].

Given the evidence that corticosteroid responsiveness is minimal in the absence of T2-driven inflammation, there is a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in patients with low T2 biomarkers. Patients with high T2 biomarkers are at risk of severe exacerbations (e.g. baseline fractional exhaled nitric oxide (FeNO) > 45 ppb predicts frequent exacerbation [17]), and in this group the key clinical question is whether this is because of non-adherence to inhaled corticosteroid treatment or whether they have relative corticosteroid-resistant T2-high asthma and require additional treatment with biological drugs that target T2 mechanisms (e.g. antibodies that inhibit interleukin (IL)-5 or IL-13 signalling). Work-strand 1 of the programme aimed to provide a clinical stratification of patient cohorts and will serve as a platform for investigative programmes in the other work-strands [18].

Aim 1
Identify non-adherence: Non-adherence to steroid treatment is often unintentional and is poorly detected by clinicians and enrolment of non-adherent patients into clinical trials complicates the interpretation of the results. Work-strand 1 aimed to develop and validate biomarkers as objective tools for assessing non-adherence to steroid treatment. Patients were tested for inhaled steroid adherence, using the fractional exhaled nitric oxide (FeNO) suppression test combined with remote inhaler monitoring technology. This test identifies inhaled steroid responsiveness and patients who are adherent but inhaled corticosteroid resistant and remain T2-biomarker high despite adequate adherence with high dose inhaled steroids (T2-high asthma) require additional treatment. Other novel biomarkers were also studied as a means to assess adherence.

Aim 2
Evaluation of a composite T2 biomarker score to optimise steroid treatment: Although individual Type 2 biomarkers (blood eosinophil count, FeNO and serum periostin) correlate with risk of asthma exacerbation and steroid response, a composite score using all these biomarkers may offer greater predictive power. RASP-UK compared a composite biomarker strategy with standard care to identify if steroids can be better targeted in severe asthma.

Aim 3
Characterise and follow up the T2-low cohort: It is now recognised that not all facets of severe asthma are driven by Type 2 effector cytokines (such as interleukins-4, -5 and -13). It was anticipated that using the composite biomarker strategy described above, we would identify patients with “T2-Low asthma”. A key focus of RASP-UK was to phenotypically characterise and compare this population with (i) the T2-high cohort and (ii) subjects with stable asthma and good symptom control on low dose corticosteroids. It was hoped that by characterising and comparing patient phenotypes, important structure/function/symptom relationships could be defined. The T2-Low cohort was to be followed-up to identify exacerbation pattern and phenotype stability.

Aim 1
Define Bronchoscopic sampling procedures: The analysis of expressed genes in airway epithelial cells is useful for defining subsets of asthma. Bronchoscopic samples from patients with T2-Low asthma will enable the analysis and identification of differentially expressed genes and other differences and thus allow us to interrogate the factors driving T2-Low severe asthma. It is probable that T2-Low severe asthma is heterogeneous and we do not currently know what drives disease in this phenotype, although ‘non-inflammatory’ structural changes may be involved. Therefore, a detailed immunopathological analysis will be performed coupled with gene expression data.

Aim
To identify novel biomarkers to predict response to Omalizumab treatment: Omalizumab is an approved treatment for severe atopic asthma which reduces asthma exacerbations. There are currently no reliable biomarkers that predict which patients will respond positively to omalizumab, however the Unbiased BIOmarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) programme has identified novel biomarkers in patients with severe asthma. These urinary biomarkers will be investigated for their predictive value with omalizumab treatment in subjects suitable for omalizumab.

Partners
The RASP-UK consortium is made up of partners from a wide range of backgrounds, including doctors and nurses who treat people with severe asthma on a daily basis, researchers, pharmaceutical partners, representatives from companies who manufacture inhalers and other treatments for asthma, and most importantly patients through Asthma UK.

The clinical centres come from across the UK and include sites in Belfast, Oxford, Leicester, Manchester, Southampton, London, Nottingham, Sheffield, Glasgow, Birmingham and Newcastle upon Tyne. Industrial partners included AstraZeneca / Medimmune, Circassia Ltd., GlaxoSmithKline, Hoffmann la Roche / Genentech Inc., Niche Science & Technology Ltd. 

Reference List

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4. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J. 1998;12:1209–18.

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10. McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, Fahy JV. A large subgroup of mild-to-moderate asthma is persistently non-eosinophilic. Am J Resp Crit Care Med. 2012;185:612–9.

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13. Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF. Systematic assessment of difficult-to-treat asthma. Eur Respir J. 2003;22:478–83.

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19. Heaney LG, et al. Composite type-2 biomarker strategy versus a symptom– risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med 2020 September 8, 2020 https://doi.org/10.1016/S2213-2600(20)30397-0