Introduction
Biologic therapies have revolutionised Severe Asthma (SA) management,
heralding a potential era of personalized medicine (1) that better
addresses SA’s heterogeneity. In the United Kingdom (UK), four biologics
are currently approved for use in SA (2). The two in longest use are the
anti-immunoglobulin E (IgE) biologic, Omalizumab (OMA) and the
anti-interleukin-5 (IL-5) biologic, Mepolizumab (MEPO). Both agents
proved highly effective in phase-III randomised controlled trials (RCTs)
(3–6) 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 SA 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 is
urgently needed (10) to better understand their place in real-life SA
management. Additionally, an evolving paradox of biologic choice places
greater onus on clinicians to “get it right 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 the
two widely used asthma biologics, OMA and MEPO, from the thoroughly
characterised, longitudinal Wessex AsThma CoHort of difficult asthma
(WATCH) (11).
MethodsWATCH is a prospective observational study of patients managed in a
tertiary 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 (REC reference:
14/WM/1226) and written informed consent was obtained for all
participants.
We conducted a retrospective study of biologic naïve patients from WATCH
who were started on OMA or MEPO between June 2006 and May 2019. Biologic
eligibility was based on National Institute for Health & Care
Excellence (NICE) guidance
(13,14)
[supplementary table E1]. Our aims were three-fold. First, to define
phenotypic characteristics of patients commencing OMA or MEPO against SA
patients who remained biologic naive. Second, to assess clinical
responses to both agents from biologic trial data and identify features
associated with response. Finally, to assess the spectrum of responses
to these biologics.
Biologic trial data were collected at baseline (first biologic visit)
and at subsequent treatment visits: 2-4 weekly for OMA and 4-weekly for
MEPO. This included Asthma Control Questionnaire-6 (ACQ6), incidence of
exacerbations (exacerbations requiring an acute oral corticosteroid
[OCS] course / increase in maintenance OCS [mOCS]), incidence of
emergency department or hospital admissions (Acute Healthcare Encounters
[AHE]), current mOCS dose and Clinic percent predicted
FEV1 (FEV1%). Hospital anxiety and
depression scale (HADS) and Asthma Quality of Life Questionnaire (AQLQ)
were collected at baseline and final visits for MEPO. Fractional Exhaled
Nitric Oxide (FENO) was collected at all MEPO visits, but only at the
baseline OMA visit. Co-morbidity, anthropometric and demographic data
were extracted from the WATCH database. Maximum peripheral blood
eosinophil count (PBE), total IgE, baseline exacerbations and AHE were
from the 12 months prior to biologic approval. Exacerbations and AHE
were annualised for comparisons.
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
either had ≥4 exacerbations or ≥1 AHE or were on mOCS in the past year
but did not commence biologic therapy 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-onset (<18 years), female/early-onset,
male/adult-onset (≥18 years), female/adult-onset] that we recently
described (15), to further characterise their phenotypic features.
Biologic response was determined by the clinical MDT (Multi-Disciplinary
Team), based on NICE guidance (13,14). For OMA, response was assessed
using the Global Evaluation of Treatment Effectiveness (GETE) (16–18).
For MEPO, response was defined as a ≥50% reduction in exacerbations or
in mOCS dose without loss of asthma control. In borderline OCS
responders, factors such as change in AHE, symptom control or
quality-of-life would additionally guide MEPO continuation. Treatment
trials typically ended at 16 weeks for OMA and 12 months for MEPO.
However, equivocal trials were extended up to 32 weeks for OMA and 18
months for MEPO.
We defined ‘super-response’ separately
for both biologics. OMA super-responders were defined as 16-week
responders who either 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 free. For MEPO, super-responders were defined as
12-month responders who either 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.
Statistical analysis was
performed with SPSS 26 (IBM Corp, NY, USA), GraphPad Prism 9 (GraphPad
Software, California, USA) and R (R Foundation, Vienna, Austria).
Continuous variables were presented as Mean (Standard deviation[SD])
or Median (Interquartile range[IQR]). Categorical data were
presented as percentage(frequency). Data were analysed using paired and
unpaired t-tests, Mann-Whitney U test, Wilcoxon-Signed Rank test,
Chi-square test, McNemar test or Fisher’s exact test as appropriate.
Multiple logistic regression (backward variable selection) was performed
using variables trending towards significance (P<0.2).
Statistical significance was set at P-value < 0.05.