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.