Benralizumab Effect on Severe Chronic Rhinosinusitis With Eosinophilic Polyposis
Condition: Chronic Rhinosinusitis (Diagnosis); Nasal Polyps; Eosinophilia
MeSH terms: Sinusitis; Nasal Polyps; Eosinophilia
Study type: Interventional
Phase: Phase 2

Summary: 
      Benralizumab will be used in a placebo controlled randomized study to treat severe chronic
      rhinosinusitis with nasal polyps
    

Detailed description: 
      Chronic rhinosinusitis (CRS) has a prevalence of more than 10% in the United States and
      Europe and is associated with several co-morbidities including asthma, acute infection, and
      obstructive sleep apnea. There are principally two forms of CRS namely with and without nasal
      polyps. CRS with nasal polyps (CRSwNP) in particular can be a severe and debilitating disease
      resulting in significant morbidity, complete anosmia, headaches, missed work, and
      hospitalizations. Not uncommonly, patients require chronic oral corticosteroids, multiple
      courses of antibiotics, and repeated surgical polypectomies to control participants' disease.
      Total health care expenditure for CRS (which includes both with and without polyps) is more
      than $60 billion annually in the United States accounting for as much as 5% of the total US
      health care budget. Annual direct and indirect costs to treat CRS in Europe is estimated to
      be similar to this amount but data is limited.

      For CRSwNP patients suffering with severe and recurrent nasal polyps there are few treatment
      options. High dose topical nasal steroids and repeated surgical procedures do not halt
      progression in many patients. Allergen immunotherapy is often non-curative in this
      population. Similarly, due to the fact that CRSwNP is not exclusively an Immunoglobulin E
      (IgE) driven process, omalizumab was shown to have mixed benefit in this population.
      Likewise, omalizumab resulted in no reduction in polyp size among patients with Aspirin
      Exacerbated Respiratory Disease (AERD).

      More typically chronic nasal polyp disease is an eosinophil mediated process. Patients with
      demonstrated elevations in serum and mucosal eosinophils tend to have more severe disease and
      higher nasal polyp recurrence rates. Clinical researchers have begun to recognize this
      connection. A recent Phase II study in Europe showed a reduction in polyp burden using
      mepolizumab anti-Interleukin (IL) 5 monoclonal antibody. Benralizumab which targets IL-5
      receptor signaling has been shown to have powerful apoptotic effects on eosinophils and may
      likely prove to be even more efficacious. Because of its unique mechanism of action,
      benralizumab may have a profound impact on reducing mucosal eosinophils resulting in great
      benefit to patients suffering with severe nasal polyps refractory to standard treatment.

      Benralizumab has been shown to be efficacious treating severe asthmatics with eosinophilia.
      The unique mechanism of action of benralizumab targets the IL-5 receptor leading to
      degradation of signaling and apoptosis. This direct effect on eosinophils leads to reduction
      of proinflammatory processes in the asthmatic airways among those with elevated eosinophil
      counts. While many subjects with allergic asthma do indeed have concomitant local and
      systemic elevations in eosinophils, the primary driver of inflammation in allergic asthmatics
      is IgE and IL-4. Allergen immunotherapy and anti-IgE therapy (omalizumab) has long been known
      to be effective in these atopic individuals. However, a significant portion of non-asthmatics
      respond poorly to these IgE targeted therapies.

      In a similar manner, chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease often
      associated with atopy and propagated by IgE/IL-4 mediated inflammation. However, more than
      50% of patients with CRSwNP have no evidence of allergen sensitivity. Nasal and sinus
      inflammation in these non-atopic individuals is often characterized by IL-5 upregulation,
      eosinophilia, leukotrienes, and more severe polyps. These individuals tend to have more
      aggressive disease requiring frequent surgeries, high dose intranasal budesonide irrigation,
      and oral steroids yet the polyps more often than not are persistent and may return post
      surgery. In a subset of patients, concomitant aspirin sensitivity can be managed with aspirin
      desensitization, however this approach is not always effective and can also be cumbersome. A
      more universal and potentially more efficient approach to treating severe polyps is to target
      eosinophils directly using a monoclonal antibody. Previous reports have shown some benefit
      targeting IL-5 ligand itself with mepolizumab but the potential benefit of directly
      eliminating eosinophils by shutting down cellular signaling with benralizumab would be
      expected to have a more dramatic effect and needs to be investigated.
    

Intervention name(s): Benralizumab; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 30mg Benralizumab will be delivered subcutaneously; Subcutaneous placebo injection
Other intervention name(s): Fasenra
Intervention MeSH terms: Benralizumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment