Efficacy of Dupilumab for Patients With Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP): a Randomized Double Blind Placebo Controlled Phase II Study

Approximately 12% of adults in the United States, United Kingdom and other industrialized nations suffer from chronic sinus disease. Corticosteroids and antibiotic regimens are often used to treat the condition but the level of evidence to justify this approach is limited and at best offers only a transient solution. Furthermore, adverse side effects from the use of long-term oral steroids and concerns about skewing of the mucosal microbiota from overuse of antibiotics make these options problematic.

Currently, there are insufficient options for the approximately 30 million patients in the US suffering from chronic sinus disease. Recent phase 3 clinical trials found that dupilumab, an anti-IL4α receptor monoclonal antibody, reduces symptoms and polyp size in individuals with CRS with nasal polyps (CRSwNP). Similarly anti-IL5 antibodies have also been shown to have modest efficacy in this group of patients. However, for the approximately 65% of individuals with non-polyp related chronic sinus disease, these agents were not evaluated and there remains few viable options for therapy.

Chronic rhinosinusitis is defined as symptoms of nasal obstruction, facial pain or pressure, and mucopurulent drainage for at least 12 weeks along with evidence of mucosal disease by radiographic evidence or rhinoscopy. At least ten endotypes have been described although there is considerable overlap in terms of mucosal morphology, allergic status, the presence of polypoid tissue, and expression of biomarkers such as cytokines, specific IgE and other proteins. It may be incorrect to assume that the effectiveness of dupilumab demonstrated for those suffering with nasal polyps is exclusive to this CRS cluster alone.

One aspect to explain the differential effects of certain drugs and biologics on the treatment of CRS relates to host nasal and sinus microbial environment. The microbiome of CRS patients has been found to have reduced diversity, increased bacterial populations, and ultimately to have less stable bacterial networks. This imbalance of the microbiome may be a potential cause for sinus inflammation. Studies have demonstrated that Propionibacterium acnes for example, acts as an important stabilizing organism in the bacterial networks. Removal of this bacterial species e.g. from antibiotic use, may allow for more pathogenic organisms such as Staphylococcus or Streptococcus to flourish leading to increased inflammation.

An example of how Staphylococcus aureus may increase inflammation is through the production of superantigen that is thought to skew nasal inflammatory responses towards a Th2 dominated disease endotype. Other groups, have concluded that the host mucosal microbiota helps predict disease severity and might also predict susceptibility to certain therapies. Indeed, treatment with certain antibiotics has shown to modulate mucosal bacterial populations leading to clinical improvement and reduced polyp formation in some patients. It is not known whether host microbial and inflammatory milieu adequately predicts polyp formation or helps predict treatment success in the presence of dupilumab. The current study will include investigation of this important exploratory outcome.