Monoclonal Biologics
Biologic therapies targeting type 2 inflammation are increasingly used in patients with severe CRSwNP, which is associated with asthma comorbidity, worse disease severity, and recurrence after surgery (Table 1 ). Several monoclonal antibodies are either approved or under development for CRS. All inhibit aspects of T2 inflammation and have minimal side effects. Use of anti-T1 or T3 monoclonal antibodies for these respectively minor CRS endotypes (in the West) has not been attempted. Such treatment, if safe, might benefit patients with T1 or T3 endotypes, especially in Asia, where they are more prevalent.
Dupilumab is a monoclonal antibody that blocks IL-4 and IL-13 by binding to the α component of their shared receptors and inhibits T2 inflammation. In two phase 3 studies of only CRSwNP patients, SINUS-24 and SINUS-52, dupilumab reduced nasal polyp size, improved symptoms including nasal congestion and anosmia, and improved quality of life in patients with severe CRSwNP 94. A pooled analysis of these studies showed that dupilumab reduced aggregate systemic corticosteroid use and nasal surgery by 76% compared to the placebo arm and substantially decreased type 2 inflammatory markers in serum and nasal secretions of patients with CRSwNP 184. Based on these studies, dupilumab was approved for the treatment of inadequately controlled CRSwNP.
Omalizumab is a humanized monoclonal that selectively binds to the Cε3 domain of IgE and prevents IgE from binding to the high-affinity IgE receptor on mast cells and basophils 185. Elevated local IgE is found in NP and is associated with local eosinophilic inflammation, severe NP, and comorbid asthma11,43,49,72,79,106 . The POLYP 1 and POLYP 2 phase 3 trials found that omalizumab reduced polyp size and improved sinonasal symptoms and quality of life in patients with CRSwNP95.
Mepolizumab is a monoclonal antibody that inhibits IL-5, the cytokine that is key in promoting eosinophil recruitment, activation and survival. Phase 3 trials have demonstrated subjective and objective efficacy and FDA approval for CRSwNP is expected late in 2021. (ClinicalTrials.gov. NCT0308579). Benralizumab is a cytotoxic monoclonal antibody targeting the IL-5 receptor that eliminates eosinophils and has undergone Phase 3 trials for CRSwNP (ClinicalTrials.gov. NCT03401229). The completed phase 3 trials reportedly met their primary endpoints at the time of this review.
Overall, although the monoclonal antibodies above are effective drugs that target key elements of T2 inflammation, their efficacy relative to each-other is presently unclear. T2 sub-endotypes likely exist, based upon anecdotal reports of variable response to these monoclonal antibodies. Intuitively, patients with eosinophil-driven disease should respond best to mepolizumab or benralizumab, while patients with disease driven by mast cells and IgE should respond best to omalizumab and perhaps dupilumab; no head-to-head trials have been performed, and no strong recommendations can be made as to which biologic to use first in a patient with T2 disease. Nonetheless, expert panels have made some recommendations for clinicians 186. There is the untested impression that dupilumab has the greatest objective efficacy and highest response rate of the currently available T2 targeting monoclonal antibodies.
The success of T2 biologics in CRSwNP established the importance of endotype targeted therapy in difficult to treat NP. Use of these drugs is only approved in T2 polyp patients with established endotype. The use of mucus samples to determine endotype is under development. Currently, the presence of asthma, AERD and serum eosinophilia (>300µl) are indicators of T2 CRSwNP in surgery naïve patients. In post-surgery patients, eosinophilic histology is definitive. T2 biologics are indicated for CRSwNP with severe symptoms despite INS and more than one oral prednisone burst per year. Questions remain about whether these drugs should be used in patients that have not undergone surgery as the surgical revision rate at 5 years is only approximately 20% 187-189. While these drugs are effective, QOL does not return to normal, and polyposis does not completely resolve94. The most effective and practical treatment regimen for high risk, multi-recurrent patients may be surgery followed by a planned post-operative biologic agent to prevent recurrence and further reduce symptom burden.