Are biologics grabbing the spotlight?
As vastly proved, initial treatment of CRS includes topical and systemic
corticosteroids, long-term antibiotics and surgical intervention.
However, some patients suffer from a recalcitrant form of disease
despite best practice. In recent years, the advancement in
pharmaceutical therapies has reached application also in CRSwNP, with
molecules (monoclonal antibodies) that specifically target the major
players in the inflammation cascade of CRSwNP [36]. For what
concerns the use of biologics, the European Forum for Research and
Education in Allergy and Airway Diseases (EUFOREA) suggested five
criteria that should be satisfied to prescribe them in CRSwNP [44].
Besides having undergone sinus surgery, three criteria have to be met
among the following: the evidence of type 2 inflammation, the need for
systemic corticosteroids in the past 2 years, a significant impairment
in quality-of-life because of the disease, reduced sense of smell and
comorbid asthma. The fact that biologics may become an alternative to
surgery is still a matter of discussion and it will be established
after their approval for CRSwNP and post-marketing surveillance phase.
The critical players that have been targeted so far are IgE, IL-5, IL-4
and IL-13, as well as some of their receptors [36]. The continuous
local activation of mast cells, basophils and dendritic cells by IgE can
be reduced by selective binding to free circulating IgE, thanks to an
anti-IgE antibody (omalizumab) [45]. Two pivotal old studies
[45,46] in a small number of patients (<30) gave
contradictory results, but very recently the first results of two phase
III clinical trials (POLYP 1 and POLYP 2) showed that omalizumab
significantly improved endoscopic, clinical and PROs in patients with
corticosteroid-refractory CRSwNP [47].
Other drugs that block circulating IL-5 (mepolizumab and reslizumab) and
therefore interrupting eosinophilic inflammation, have undergone testing
through randomized controlled studies: the only large study that was
conducted with 105 severe CRSwNP patients is by Bachert et al. [48],
showing that mepolizumab reduced the need for sinonasal surgery compared
to placebo. Significant improvement in symptoms (rhinorrhea, nasal
blockage and hyposmia), quality of life (by means of Sino-nasal Outcome
Test, SNOT-22, questionnaire), as well as increase in Peak Nasal
Inspiratory Flow (PNIF) in patients treated with mepolizumab. Similarly,
blood eosinophils decreased. Results of phase 3 trials for mepolizumab
in CRSwNP are expected to be published within a year [36]. Also,
RCTs on benralizumab, a monoclonal antibody directed towards the alpha
subunit of IL-5 receptor (IL-5Rα), are ongoing.
Interleukin-4 (IL-4) and interleukin-13 (IL-13) have overlapping
biological effects because of their partly shared receptor complex
[29]. IL-4 may interact with either a type I receptor (made of IL-4
receptor alfa, IL-4Rα, and the common γ-chain of the IL-2R) or a type II
receptor (made of IL-4Rα and an IL-13 binding chain, IL-13Rα1). This
type II receptor complex is also a functional receptor for IL-13, which
is the reason or IL-4/IL-13 common pathways and functional properties
[49]. Dupilumab is a monoclonal antibody against the IL-4Rα that
inhibits both IL-4 and IL-13 signaling. Dupilumab significantly improved
nasal polyp score (NPS), nasal congestion or obstruction, and sinus
Lund-Mackay CT scores in two phase-3 big trials (SINUS-24 and SINUS-52)
[50]. At the moment, it is the only monoclonal antibody approved for
the treatment of CRSwNP [1,36].