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.