Discussion
This study represents the first randomized clinical trial designed to
evaluate the use of benralizumab for nasal polyps. We showed that 30mg
of benralizumab administered in four subcutaneous doses over a 20 week
period significantly reduced nasal polyp size and nasal blockage score
and reversed the impaired sensation of smell for the majority of
patients. The reduction in nasal polyp size was evaluated by CT scan and
endoscopy with independent confirmation by three blinded investigators.
Benralizumab was well tolerated with no significant adverse events
reported. Taken together, these observations suggest that benralizumab
may have a role in the treatment of patients with severe CRSwNP.
Both benralizumab and placebo resulted in improved SNOT-22 scores,
although by week 4 of treatment and upon regression towards the mean,
only the benralizumab group continued to improve. One explanation for
the initial SNOT-22 improvement in the placebo arm is that these
patients received almost twice the amount of triamcinolone nasal spray
rescue medicine compared to the benralizumab group. Furthermore, the
nasal blockage score, arguably the most important SNOT-22 survey metric
in this cohort, improved significantly only with benralizumab.
Benralizumab resulted in improved sense of smell in all but one patient.
For many patients sense of smell is the single most relevant clinical
outcome.(13, 25) Future studies will need to address whether or not
polyp size reduction follows the same course as SNOT-22 scores in that
an initial reduction is followed by a plateau phase or if there is
gradual continued reduction in polyp size over time. A large
international phase 3 study on the effect of benralizumab on nasal
polyps is currently underway designed to address this and other
questions.
The absolute reduction in nasal polyp size was similar to that seen with
other anti-IL-5 and anti-IL-4R biologic mAbs.(11, 15, 26) Benralizumab
reduced mean nasal polyp size by approximately one point (range 0-4 each
side). As with others studies of biologics or intranasal steroids, even
a seemingly small decrease in polyp size for example from a score of 3
to a score of 2 can be associated with very significant clinical
improvement.(11, 15, 26, 27)
We chose to enrol only NP patients refractory to standard therapies who
had at least one previous polypectomy because this represents a group of
patients with severe debilitating disease and high healthcare
utilization. We do not know what the effects of benralizumab would be on
patients with milder disease or those who may have recently underwent
polypectomy. All patients required a blood eosinophil count of 300/µl or
more for entry into our study but some improvement in nasal polyp scores
were seen across a range of values.
Notably, all participants with a blood eosinophil count greater than
700/µl improved with benralizumab. Conversely, while a few aeroallergen
sensitive subjects noted some reduction in polyp size, 5/5 patients with
negative skin prick testing improved with benralizumab, although this
represented only a small subset of the overall patient population
studied. The ratio of blood eosinophils to SPT was highly correlated
with a reduction in polyp size as demonstrated by endoscopy and CT scan.
In other words, all patients with a high eosinophil count and low number
of positive allergen skin prick tests improved with benralizumab. This
correlation appears to be driven largely by one patient with a blood
eosinophil count greater than 1500/µl, however even with removal of this
outlier, the one-tailed Spearman rank correlation between eos/SPT and
polyp size remains significant (P=0.024). Nonetheless, our data will
need to be replicated in larger studies in order to consider
incorporating these findings into clinical practice.
It is unknown if these outcomes associated with allergen skin prick
testing would hold true for specific IgE measured in serum since both
the physiological capacity to degranulate mast cells and basophils and
the diagnostic sensitivity is superior with SPT. Benralizumab is known
to have affinity for the IL-5 receptor on both eosinophils and basophils
so inherent differences associated with detection of specific IgE in the
skin versus the blood may have relevance when evaluating nasal mucosal
biology.
Whether or not the Eos/SPT ratio helps identify a true categorical CRS
endotype, defined for example as a high IL-5 and low IL-4 subgroup,
still needs to be determined. Our study was not powered to delineate
these CRS subgroups in detail. However, several groups have discussed
the importance of subdividing CRS patients into various endotypes based
on a number of biological markers such as type 1 cytokines (IL-12 and
interferons), type 2 cytokines (IL-5, IL-4, IL-13), type 3 cytokines
(IL-17), eosinophilic cationic proteins, IgE synthesis, fibrin products,
TLR expression, microbial populations, and many others.(28-32) A recent
National Institute of Allergy and Infectious Disease workshop and
position paper highlighted the need for novel research into treatment
and diagnosis strategies for CRSwNP in the era of new biologics.(25)
Others have argued further that differentiating CRS based on the
presence of polyps alone falls short of fully characterizing the complex
and multifaceted inflammatory cascade in general.(33) Indeed, clinically
robust and practical biomarkers are scarce. With trends towards
increased precision medicine and an expanding array of highly targeted
biologics, it has become increasingly important to identify simple tools
to help clinicians determine which treatment is best for their patients.
The fact that our study showed a correlation between improved efficacy
of benralizumab in patients with a higher eosinophil counts and low
allergen sensitivity as determined by SPT does not exclude the
possibility of this treatment being effective for other patient subsets.
In addition, blood eosinophil counts are likely to fail as a direct
surrogate for nasal mucosal inflammation. Laidlaw et. al. showed that a
reduction of blood eosinophils alone with dexpramipexole inherently had
no effect on nasal polyp size.(34) Nonetheless, the effect of
benralizumab may go beyond that of mere blood eosinophil depletion in
part based on the presence of IL-5 receptor on the surface of basophils
and an associated downregulation of other inflammatory cells.
Indeed, our demonstration that patients with high eosinophils responded
well to benralizumab is not unexpected. Asthma studies have also shown
that while benralizumab is effective across a broad range of blood
eosinophil counts, there was a trend towards greater efficacy with
higher baseline eosinophil levels.(19) Clearly, more work needs to be
done to determine which biomarkers are both predictive and practical for
clinicians. Nonetheless, our study suggests that currently available
tools such as blood eosinophil count and allergen skin prick testing may
help provide some initial guidance until more sophisticated biomarkers
are developed. This information, along with knowledge about concomitant
comorbidities such as asthma, aspirin sensitivity, or atopic dermatitis
may help physicians select an appropriate therapy for their patients.
The primary limitation in this study is the modest sample size.
Randomization resulted in balanced distribution of most but not all
baseline characteristics. As such, the percentage of aspirin sensitive
subjects at baseline were higher in the placebo group. It is possible
that this could have affected the outcome.
We also noted a transient improvement in SNOT-22 among the placebo
group. Nonetheless, benralizumab treated patients significantly improved
across all major and minor indices including endoscopic polyp score, CT
scan, SNOT-22, nasal blockage score and smell test. Future studies will
need to determine if polyp size and symptoms continue to improve past
twenty weeks therapy and if benralizumab ultimately reduces the
frequency of polypectomies and the need for corticosteroids.
In summary, our study is the first randomized clinical trial of
benralizumab for the treatment of nasal polyps. Benralizumab
administered 30mg SC over a 20 week period significantly reduced nasal
polyp size, nasal blockage score and improved the sensation of smell for
the majority of patients we treated with severe CRSwNP. Larger studies
will need to be performed to confirm that benralizumab can be added to
our treatment armament for this debilitating disease.