Real- world Omalizumab and Mepolizumab treated difficult asthma phenotypes and their clinical outcomes

Background: Omalizumab and Mepolizumab are biologic drugs with proven efficacy in clinical trials. However, a better understanding of their real- world effectiveness in severe asthma management is needed. Objectives: To better understand the real- world effectiveness of Omalizumab and Mepolizumab, elucidate the clinical phenotypes of patients treated with these drugs, identify baseline characteristics associated with biologic response and assess the spectrum of responses to these medications. Methods: Using real- world clinical data, we retrospectively phenotyped biologic naïve patients from the Wessex AsThma CoHort of difficult asthma ( N = 478) commenced on Omalizumab ( N = 105) or Mepolizumab ( N = 62) compared to severe asthma patients not receiving biologics (SNB, N = 178). We also assessed multiple clinical end-points and identified features associated with response. Results: Compared to SNB, Omalizumab patients were younger, diagnosed with asthma earlier, and more likely to have rhinitis. Conversely, compared to SNB, Mepolizumab patients were predominantly older males, diagnosed with asthma later, and more likely to have nasal polyposis but less dysfunctional breathing. Both treatments reduced exacerbations, Acute Healthcare Encounters [AHE] (emergency department or hospital admissions), maintenance oral corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6) scores. Omalizumab response was independently associated with more baseline exacerbations ( p = .024) but fewer AHE ( p = .050) and absence of anxiety ( p = .008). Lower baseline ACQ6 was independently associated with Mepolizumab response ( p = .007). A composite group of non- responders demon-strated significantly more psychopathologies and worse baseline subjective disease compared to responder groups. Conclusions and Clinical Relevance: In a difficult asthma cohort, Omalizumab and Mepolizumab were used in


| INTRODUC TI ON
Asthma biologic therapies herald a potential era of personalized medicine 1 that better addresses severe asthma's heterogeneity. In the United Kingdom (UK), four biologics are currently approved for use in severe asthma. 2 The two in longest use are the anti-immunoglobulin E (IgE) biologic, Omalizumab and the antiinterleukin-5 biologic, Mepolizumab. Both agents were highly effective in phase-III randomised controlled trials (RCTs) [3][4][5][6] and have been widely adopted into clinical practice. However, RCT populations are not reflective of real-world patients. 7,8 Brown et al. highlighted that only 9.8% of their severe asthma cohort met enrolment criteria of Phase-III asthma biologic RCTs. 9 Thus, as the portfolio of biologics continues to expand, real-world data on these drugs are urgently needed 10 to better understand their place in real-life severe asthma management. Additionally, an evolving paradox of biologic choice places a greater onus on clinicians to "get it right the first time", to save costs and improve patient outcomes. To guide asthma biologic selection, it is imperative to understand patient phenotypes best suited for individual drugs, identify features associated with response, and also consider how best to judge clinical impact of these therapies. Therefore, to help address these needs, we present parallel real-world clinical data on two widely used asthma biologics, Omalizumab and Mepolizumab, from the thoroughly characterized, longitudinal Wessex AsThma CoHort of difficult asthma (WATCH). 11

| ME THODS
WATCH is a prospective observational study of patients managed in a tertiary difficult asthma clinic at University Hospital Southampton, UK with "high dose therapies" and/or "continuous or frequent use of oral corticosteroids (OCS)" as per the British Thoracic Society Adult Asthma Management Guidelines 2016. 12 Detailed study methodology is described elsewhere. 11 The study had ethical approval from the West Midlands -Solihull Research Ethics Committee (4) Assess the spectrum of responses to these biologics.
Biologic eligibility was based on conventional criteria following the National Institute for Health & Care Excellence (NICE) guidance. 13,14 Briefly, for Omalizumab, 13   We defined 'super-response' separately for both biologics, given the separate eligibility and continuation criteria. Omalizumab superresponders were defined as 16-week responders who had the top quartile of percentage reduction in mOCS dose while being exacerbation and AHE free; or if not on mOCS, were exacerbation and AHE multidimensionally efficacious. Certain baseline clinical characteristics were associated with poorer biologic responses, such as psychological co-morbidity, which may assist clinicians in biologic selection. These characteristics also emphasize the need for comprehensive approaches to support these patients. free. For Mepolizumab, super-responders were defined as 12-month responders who had the top quartile of percentage reduction in mOCS dose, while having a synchronous reduction in exacerbations; or if not on mOCS, had the top quartile of percentage reduction in exacerbations.
To describe the biologic-naïve characteristics of the biologic treated groups, a common comparator 'severe asthma, non-biologic' (SNB) group was extracted from WATCH. SNB subjects (N = 178) were participants who in the past year either had ≥4 exacerbations or ≥1 AHE or were on mOCS, but did not commence biologics during the study period. Comparisons were made using baseline biologic data for the biologic treated groups and WATCH enrolment data for the SNB group. Additionally, biologic treated groups were mapped onto four age-of-onset/sex clinical clusters (male/early-

Groups vs SNB (comparator) group
Compared to SNB subjects, neither biologic groups were significantly different in terms of baseline exacerbations or AHE (Table 1 and Table 2). However, the biologic treated groups had significantly higher FENO, worse lung function and more mOCS dependency (Table 1 and Table 2).
Compared to SNB subjects, Omalizumab treated subjects had a significantly younger age of asthma onset (  Conversely, compared to SNB subjects, Mepolizumab treated subjects had a significantly higher maximum PBE (Table 2), were older, diagnosed with asthma later in life, and predominantly male.
Additionally, they had a significantly higher prevalence of nasal polyposis and nasal (polyps/sinus) surgery but less dysfunctional breathing.

| Omalizumab responders, non-responders and super-responders
Based on our definitions, of Omalizumab subjects who completed trials (Figure 1)

| Mepolizumab responders, nonresponders and super-responders
Based on our definitions, among Mepolizumab subjects who completed their trials (Figure 1) Summary phenotypic features of Omalizumab and Mepolizumab treated patients and features independently associated with response and super-response to these drugs is displayed in Figure 3.

| Age-of-onset/sex stratification of biologic use
Within our biologic (Omalizumab + Mepolizumab) cohort, the female/early-onset cluster was most prevalent, while the male/ early-onset group was the least. Although biologic use across these phenotypes (Table 4) was significantly different, there was no statistically significant difference in response for either biologic across these phenotypes.

| Alternative assessments of biologic outcomes
The 'Global Evaluation of Treatment Effectiveness' tool used in Omalizumab (Figure 4a)

| DISCUSS ION
This study adds further insight into a growing body of realworld data on the use of biologic drugs in more severe asthma. It uniquely characterised the parallel biologic naïve characteristics of Omalizumab and Mepolizumab treated subjects against a common comparator that remained biologic naïve (SNB) within the same difficult asthma cohort. A key finding was that despite potentially Note: Early-onset: age of asthma onset<18 years. Adult-onset: age of asthma onset ≥18 years. a those who completed biologic trials, i.e.: did not withdraw due to any reason. A= Chi-squared tests were performed to assess the distribution of the four age-of-onset/sex clusters across both biologics. B= Chi-squared tests were performed to assess biologic response to Omalizumab across the four age-of-onset/sex clusters. C= Chi-squared tests were performed to assess biologic response to Mepolizumab across the four age-of-onset/sex clusters. Our study had limitations. Inherent to real-world observational studies, we had some missing data. However, real-world data capture is representative of clinical populations receiving these treatments. Our report is also limited by the small numbers in the Mepolizumab group, which prevented us from uncovering whether the different age-of-onset/sex phenotypes had differing response predictors. Therefore, future studies are needed to clarify these findings and further explore age-of-onset/sex-related signals. Our study had several strengths. We report detailed real-world clinical outcomes on both Omalizumab and Mepolizumab in parallel, against a non-biologic comparator in a difficult asthma cohort, adding to the growing real-world dataset on these drugs. Additionally, our cohort

F I G U R E 4
represents an extensively characterized difficult asthma population from a wide geographical catchment, enhancing the generalisability of our findings. This allowed mapping of previously described clinical clusters onto our data, consolidating our observations. We also undertook a pooled analysis of the non-responder group and explored other definitions of response in Mepolizumab, compared to Omalizumab.

| CON CLUS ION
In summary, in this real-world difficult asthma cohort, Omalizumab and Mepolizumab were used for distinct SA phenotypes in which they were both multidimensionally effective. Among these phenotypes, we identified some features independently associated with response, which may assist clinicians. In turn, those findings reiterated the importance of detailed characterisation and addressing treatable traits alongside consideration of biologics use in more severe asthma. To further enhance the personalized and optimal use of biologic therapies, future research should develop a deeper endotypic understanding of asthma biologic need and responsiveness.

CO N FLI C T O F I NTE R E S T
PD received a non-promotional grant from Novartis for the WATCH study for data entry clerk funding. PH is an employee of

ACK N OWLED G EM ENTS
The authors thank the WATCH participants and the WATCH study team who conducted this study. They also acknowledge the support of the National Institute for Health Research (NIHR) Southampton Biomedical Research Centre and NIHR Clinical Research Facility,