A New Era for Severe Asthma: RASP-UK First Publication

In a significant step towards personalising treatment for some of the most challenging respiratory cases, the UK Refractory Asthma Stratification Programme (RASP-UK) marked its inception with a pivotal publication in the journal Thorax [1]. This first article, titled "Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)," laid out an ambitious and logical roadmap to tackle the immense burden of severe asthma by moving beyond the traditional "one-size-fits-all" approach [1]. The programme, accessible at www.rasp.org.uk, represents a concerted, multi-centre effort to revolutionise both clinical management and the future of drug development for this complex condition.

The Unmet Need in Severe Asthma and the Case for Stratification

Severe refractory asthma, while affecting a small percentage of asthma patients (around 2-5%), accounts for a disproportionately large share of healthcare costs and patient morbidity [2]. For decades, the standard of care has involved a stepwise escalation of corticosteroid (CS) therapy, both inhaled and oral, to control symptoms. However, this strategy has fundamental flaws. It fails to recognise that ‘asthma’ is not a single disease but a collection of heterogeneous inflammatory endotypes [3].

The RASP-UK protocol paper highlighted a critical knowledge gap: prior mechanistic studies had not stratified patients based on their underlying inflammatory phenotype [1]. This is particularly crucial in the context of Type 2 (T2) inflammation. While approximately 50% of asthma patients have T2-high disease, characterised by eosinophilic airway inflammation driven by cytokines like IL-4, IL-5, and IL-13, the pathophysiological mechanisms in the remaining T2-low population are poorly understood [4]. This group often shows little to no response to CS therapy, meaning they are exposed to high doses of medication with significant side effects for little to no clinical benefit [5].

A Three-Pronged Strategy for a Paradigm Shift

Funded by the Medical Research Council (MRC) under its stratified medicine initiative, which provided a £4.8 million boost to asthma research, RASP-UK was designed to dissect the reasons for CS treatment failure and create a new model for patient care [6]. The programme's initial publication detailed a three-pronged approach to stratification:

1. Objectifying Adherence to Corticosteroids: A major, often hidden, problem in managing severe asthma is non-adherence to medication. It is estimated that 30-50% of patients with difficult-to-control asthma do not take their prescribed inhaled CS as directed [7]. This non-adherence can mimic CS-resistant disease, leading clinicians to inappropriately escalate therapy or prescribe expensive new biologic drugs to patients who might be well-controlled on their existing inhaled regimen. RASP-UK proposed using remote monitoring technologies and biomarker-based assessments, such as the " fractional exhaled nitric oxide (FeNO) suppression test," to objectively identify non-adherence and differentiate it from true treatment resistance [1][8]. This is a pre-requisite for optimising therapy and ensuring new treatments are reserved for those who truly need them.
2. Optimising Corticosteroid Dose with a Composite Biomarker Strategy: The cornerstone of the programme is a randomised, multi-centre trial comparing standard care with a novel strategy that titrates CS dose based on a composite biomarker score [1]. This composite score uses three easily measurable markers of T2 inflammation: FeNO, blood eosinophil count, and serum periostin. The RASP-UK team had previously shown that, individually, these biomarkers correlate with exacerbation risk, but using them together provides a powerful tool to predict which patients are likely to benefit from CS and, crucially, in whom CS can be safely reduced [9]. The goal is to minimise CS exposure in patients with T2-low inflammation, thereby reducing morbidity from side effects, while ensuring adequate dosing in those with T2-high, CS-responsive disease. This process directly addresses the question of what proportion of patients maintain persistent symptoms without eosinophilic inflammation after progressive CS withdrawal.
3. Characterising the "Unmet Need" – T2-Low Severe Asthma: By optimising CS therapy and identifying truly adherent patients, RASP-UK aims to cleanly delineate two distinct populations: those with persistent T2-high inflammation (requiring novel biologic therapies) and those with T2-low disease. This latter group represents a major unmet medical need, with few current treatment options. The programme is designed to intensively deep-phenotype these T2-low patients using bronchoscopy, transcriptomics, and microbiomic profiling to understand the underlying structure/function/symptom relationships and identify new therapeutic targets [1].

A Collaborative Infrastructure for the Future

A key element of the RASP-UK vision, as outlined in its first publication, is its interactive partnership with the pharmaceutical industry [1]. By creating a well-characterised, stratified patient population across the UK's major severe asthma centres, the consortium provides a unique and powerful resource for accelerating the development of new therapies. This infrastructure allows for more efficient Phase 2 proof-of-concept studies, where drugs targeting specific biological pathways (whether T2 or non-T2) can be tested in the patient population most likely to respond.

In conclusion, the first RASP-UK publication was more than just an announcement; it was a declaration of intent. It set out a logical, clinically focused framework to tackle the complexity of severe asthma head-on. By integrating objective adherence monitoring, biomarker-guided CS optimisation, and deep phenotyping, RASP-UK has established itself as a world-leading collaborative infrastructure, poised to create a lasting paradigm shift in asthma care in the UK and beyond.

References

1. Heaney LG, Djukanovic R, Woodcock A, Walker S, Matthews JG, Pavord ID, et al. Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax. 2016 Feb;71(2):187-9.
2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, Available from: https://ginasthma.org/. Source: GINA provides the epidemiological context for severe asthma prevalence and its disproportionate impact on healthcare resources.
3. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012 May 4;18(5):716-25.
4. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015 Jan;15(1):57-65.
5. Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007 Dec;62(12):1043-9.
6. Medical Research Council. Stratified medicine in the UK: building the evidence base. Swindon: MRC; 2014. Source: The MRC's public announcement of the stratified medicine initiative funding, including the RASP-UK award.
7. Gamble J, Stevenson M, Heaney LG. A study of a multi-level intervention to improve non-adherence in difficult to control asthma. Respir Med. 2011 Sep;105(9):1308-15. DOI: 10.1016/j.rmed.2011.03.019.
8. McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2012 Dec 1;186(11):1102-8..
9. Pavord ID, Shaw DE, Gibson PG, Taylor DR. Inflammatory to assess airway diseases. Lancet. 2008 Sep 20;372(9643):1017-9.