An exploratory study to assess the effect of benralizumab on small airway obstruction in patients with severe asthma using functional respiratory imaging

More than 300 million people worldwide suffer from asthma. It is a chronic
respiratory disease characterized by airway inflammation, variable airway
obstruction and bronchial hypersensitivity. Severe asthma is defined as asthma
that requires treatment with high-dose inhaled corticosteroids plus a second
controller and / or systemic corticosteroids to prevent it from becoming
"uncontrolled" or remaining "uncontrolled" despite this therapy [1]. The
prevalence of severe asthma is approximately 3% to 13% of all asthma patients.
It is a heterogeneous condition consisting of phenotypes such as eosinophilic
asthma.

The treatment of severe eosinophilic asthma has been significantly improved
with the use of biologicals. Biologicals have been found to reduce the symptoms
of severe asthma, improve lung function, reduce the use of oral
corticosteroids, and improve patients' quality of life. The biomarkers for
predicting the efficacy of biological drugs are not yet clear. In addition, it
is an expensive treatment and there is currently no consensus on the length of
treatment with biologics.

One of the biologicals is benraluzimab, which is an anti-eosinophil, humanized,
afucosylated, monoclonal antibody (IgG1, kappa). It binds with high affinity
and specificity to the alpha subunit of the human interleukin-5 receptor
(IL-5Rα). The IL-5 receptor is specifically expressed on the surface of
eosinophils and basophils. This leads to eosinophil and basophil apoptosis
through enhanced antibody-dependent cell-mediated cytotoxicity, which reduces
eosinophilic inflammation. Benralizumab treatment results in almost complete
depletion of blood eosinophils within 24 hours of the first dose, which
persists for the treatment period [2].

In two large studies [3, 4] benralizumab treatment significantly reduced asthma
exacerbations, improved lung function and improved asthma symptoms in patients
with severe uncontrolled asthma and baseline blood eosinophil counts of >= 300
cells / µl. Benralizumab-treated patients with severe previously uncontrolled
eosinophilic asthma (defined by a baseline blood eosinophil count >=150 cells /
µl) also experienced a 75% decrease from baseline in the median dose of oral
corticosteroids (OCD) versus 25% with placebo. These patients also experienced
a 70% reduction in the mean annual rate of exacerbation compared to placebo (p
<0.001) [5].
Benralizumab is approved for use in Canada, Europe, Japan, and the United
States. In Europe it is indicated for the adjunctive maintenance treatment of
patients with severe asthma aged 12 years and older with an eosinophilic
phenotype.
Benraluzimab is now part of standard care for patients with severe eosinophilic
asthma. Unfortunately, we still know too little about the locoregional effects
during treatment and not all patients are responders to this costly treatment.


The classic lung function tests, especially FEV1, are far from sensitive to
gain more insight into the pathophysiological changes during benralizumab
treatment. Functional Respiratory Imaging (FRI) provides a lot of information
about the locoregional changes in the airways. It offers the possibility for
improved visualization of anatomical structures such as; airways, lobe volumes
and blood vessels. Computer-based flow simulations with a three-dimensional
element add functionality to the CT images.

Several clinical studies using this FRI technology have been conducted and have
yielded important new information. FRI makes it possible to detect diseased
airways and lung structures very early in their development and to describe the
relationship between diseased and healthy lungs. In respiratory diseases, such
as asthma and COPD, the study of changes in airway geometries [6-9] (including
distal airways) with related regional resistance patterns and flow distribution
has provided new insights into disease progression and the impact of inhaled
and systemic treatment of the structure and function of the airways. The
classic lung function tests [10], especially FEV1, are far from sensitive to
gain more insight into the pathophysiological changes during treatment.
Especially the distal airway resistance is significantly increased in patients
with asthma, which is not measurable with spirometry.

A study in 24 stable asthma patients as defined by the GINA guidelines (Global
Strategy for Asthma Management and Prevention) with extrafine beclomethasone /
formoterol [11] showed that FRI changes significantly correlated with
clinically relevant improvements. FRI was used to gain insight into the
mechanism of action of inhalation medication. At 6 months, the entire
population showed improvement in pre-bronchodilation imaging parameters,
including resistance to small airway volumes and asthma control score. Changes
in small airway volume were correlated with changes in asthma control score (p
= 0.004). Forced expiratory volume in 1 s (p = 0.044) and exhaled nitric oxide
(p = 0.040) also improved. Functional imaging provided greater detail and
clinical relevance compared to lung function tests, especially in the
well-controlled group where only functional imaging parameters showed
significant improvement, while the correlation with asthma control score
remained. This indicates that functional imaging is a useful tool for sensitive
assessment of changes in the respiratory system after asthma treatment. The
locoregional insights using FRI can be used to personalize therapy for patients
with severe eosinophilic asthma.

The aim of this study is to use Functional Respiratory Imaging (FRI) as a
biomarker to get a deeper insight into regional changes in the distal bronchial
and central bronchial airways of asthmatic patients on benralizumab treatment.
This is the first study using FRI in patients with severe asthma treated with a
biological looking at the airway structure and function. This insight will
provide us relevant information about treatment efficacy in asthmatic patients.

The primary objective of this study is to investigate the effect (and the onset
of this effect) of benralizumab on specific image based airway volumes (SiVaw)
and resistance (SiRaw) in subjects with severe eosinophilic asthma. Absolute
change in specific airway volume (siVaw) at FRC & TLC during treatment with
benralizumab after 4 and 12 weeks · Absolute change in specific airway
resistance (siRaw) at FRC & TLC during treatment with benralizumab after 4 and
12 weeks.

The secondary objectives are to evaluate other FRI parameters and to correlate
FRI outcomes with other clinical parameters.

• FRI parameters (absolute change in values or percent predicted at baseline,
after 4 and 12 weeks of treatment): airway wall volume, air trapping, image
based lobe volumes: iVlobes ,internal lobar airflow distribution
• Lung function
• Blood eosinophil count
• Exercise tolerance
• Dyspnoea, using ACQ (Asthma Control Questionnaire) and SGRQ (St. George*s
Respiratory Questionnaire)

This is a single-centre exploratory longitudinal study, 20 patients with severe
eosinophilic asthma will be included. Each patients will be treated with
benralizumab 30 mg once every 4 weeks subcutaneous injected (in total 3
injections per patient). This treatment is provided from according to regular
standard of care. During this period we will observe clinical parameters,
spirometric parameters, eosinophil counts and HRCT changes.The total duration
of the study is 16 weeks.

Fasenra is available as a solution for injection in pre-filled syringes and
pre-filled pens. It can only be obtained with a prescription and treatment
should be started by doctors with experience in the diagnosis and treatment of
severe asthma.

The recommended dose is 30 mg injected under the skin of the thighs or belly
every 4 weeks for the first 3 doses, and every 8 weeks afterwards. If the
injection is given by a doctor or carer, it can also be given under the skin of
the upper arm. During this study each patient will receive 3 injections.

The burden consists of: extra visits to the hospital (5 or 6 times, depending
on whether screening and visit 1 can be combined, instead of 4 times with usual
care. This takes place during 12 weeks, from which the first visit in the 30
days prior to this.
Physical examination, lung function bladder tests, blood collection and
completing questionnaire (ACQ and SGRQ) are performed 3 times with usual care
to indicate and monitor the treatment, now 4 or 5 times, depending on whether
screening and visit 1 can be combined. The lung function tests are somewhat
more extensive than standard (lasting 1 hour instead of half an hour per
examination). Lung function testing is non-invasive and not invasive. The SGRQ
questionnaire has 76 items (10 minutes). A blood sample is stressful to some
extent, but 1 or 2 extra, with at least 1 or more weeks in between, is not much
extra stressful on top of the burden that is already there. A 6-minute walking
test is not stressful for this category of patients. All the participant in the
study will make an investment of time by participating.
There is a small, but not absent risk to which the subjects are exposed in the
form of ionizing radiation (total 9 mSv). This is explained in the patient
information folder. There is no other way to answer the research question. The
maximum effort was made to keep the burden on the test subjects as low as
possible.