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Pang, Yik Lam (2022) Predicting response to monoclonal antibody in severe asthma. PhD thesis, University of Nottingham.

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Abstract

Introduction

Severe asthma is a chronic debilitating condition affecting approximately 4-10% of all patients with asthma in the UK. The traditional step-approach to treating patients with severe asthma does not account for the complexity of this condition. Severe asthma patients are often given multiple treatments, leaving them with ongoing inadequately controlled symptoms and adverse effects from high-intensity medication.

The appreciation of molecular pathways leading to eosinophilic inflammation in the airways, and the association of this to an asthma phenotype with increased exacerbation tendency and oral steroid dependence, has revolutionised the treatment of severe asthma. Anti-IL5 therapies are effective at reducing the steroid burden in patients with severe eosinophilic asthma.

However, approximately 30% of patients do not respond to treatment at the end of 12 months, a treatment period endorsed by the National Institution for Health and Care Excellence in the UK. The delivery of anti-IL5 therapies is costly, and not without risk. Therefore, a robust early predictor of a 12-month response is needed.

The aim of this thesis is to explore mechanisms of poor response to one of the anti-IL-5 therapies licensed in the UK, Mepolizumab, from a clinical, serum cytokine and immunogenic perspective.

Methods

A prospective observational cohort study was performed, obtaining clinical demographics, serum samples, and patient-reported outcomes on all patients initiating on Mepolizumab through the standard of care at the Nottingham University Hospitals NHS Trust.

Serum cytokine levels representing Type 1, 2, and 17 inflammation were measured using Luminex. Immunogenicity testing to Mepolizumab was outsourced to a GlaxoSmithKline owned organisation to protect the proprietary assay.

Results

Improvement in the Severe Asthma Questionnaire (SAQ) score by the minimally clinically important difference (0.50) in the first 12 weeks of treatment led to a 6-fold increase in odds of responding to Mepolizumab (OR 6.75, CI: 1.51-30.16, p=0.012).

Serum cytokine levels at baseline or 12 weeks did not have predictive effect on treatment response to Mepolizumab.

Lastly, prognostic modelling based on drug antibody levels was not feasible due to the small number of patients with anti-Mepolizumab antibodies identified by the assay in this study.

Conclusion

Overall, this study identified the SAQ as a potentially useful tool to use in adjunct with current standard practice to guide treatment decisions. Further validation of this tool to establish its sensitivity and specificity in the UK severe asthma cohort initiating Mepolizumab is needed.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Shaw, Dominick E. Sayers, Ian
Keywords:	Severe Asthma; Monoclonal Antibodies; Predictors of Response; Biomarkers
Subjects:	W Medicine and related subjects (NLM Classification) > WF Respiratory system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	69972
Depositing User:	Pang, Yik
Date Deposited:	14 Oct 2022 10:00
Last Modified:	14 Oct 2022 10:00
URI:	https://eprints.nottingham.ac.uk/id/eprint/69972

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