Chronic rhinosinusitis with nasal polyps (CRSwNP), an important phenotype of chronic rhinosinusitis,1, 2 has an estimated prevalence of 4·2% in the USA and 4·3% in Europe.3, 4 The clinical, economic, and human burden of this condition is poorly recognised despite the high symptom burden, troublesome and difficult-to-treat loss of smell,5, 6, 7 high rates of recurrence or relapse of nasal polyps after surgery, frequent comorbid late-onset asthma, and poor health-related quality of life.8 CRSwNP predominantly displays type 2 inflammatory signatures including interleukin (IL)-4, IL-5, and IL-13, and infiltration of nasal polyps by eosinophils, basophils, and mast cells.9, 10 Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (also termed Samter's triad, aspirin-exacerbated respiratory disease in the USA, or N-exacerbated respiratory disease in Europe) is a disease phenotype described as aspirin or NSAID hypersensitivity, asthma, and CRSwNP and is associated with a type 2 inflammatory reaction. Asthma and NSAID-exacerbated respiratory disease are frequent type 2 inflammatory comorbidities, with asthma occurring in up to 65% and NSAID-exacerbated respiratory disease occurring in up to 16% of patients with CRSwNP.11, 12, 13, 14 Patients with CRSwNP and comorbid asthma (with and without NSAID-exacerbated respiratory disease) have more severe disease, characterised by high nasal polyp scores, recurrence of nasal polyps after surgery, frequent systemic corticosteroid dependence, poor asthma control, and higher costs and use of health-care resources.15
Novel therapies to improve disease control are needed to spare patients from systemic corticosteroids and repeated sinus surgery. Current standard-of-care options for CRSwNP1, 2 have limitations. Intranasal corticosteroids are the first line of therapy but have small effects on polyp size and symptoms. When symptoms worsen, systemic corticosteroids provide short-term efficacy,16 but adverse effects prevent long-term use. When pharmacological therapy is unsuccessful, surgery can be effective but, without control of the underlying inflammation disease, recurrence is common,17 resulting in repeated courses of systemic corticosteroids and surgery in a subgroup of patients with nasal polyps. A therapy that directly targets the fundamental type 2 inflammation driving this disease might provide the opportunity to offer an effective and well tolerated option that also addresses common comorbid, substantial type 2 inflammatory diseases such as asthma.
Research in context
Evidence before this study
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease with high disease burden and poor quality of life. In a subgroup of patients with CRSwNP and severe type 2 inflammation, typically associated with comorbid late-onset asthma and disease recurrence after surgical therapy, disease control cannot be achieved by existing standard of care. We searched MEDLINE (via PubMed) and Embase for articles from database inception up to Aug 4, 2016, using search terms including “nasal polyposis”, “chronic rhinosinusitis”, “chronic rhinosinusitis with nasal polyps”, “AERD”, “NSAID-ERD”, “Samter's”. Additionally, we used the Cochrane Library to search other databases, including the Cochrane Central Library of Controlled Trials. Grey literature and other resources were hand-searched to identify any other relevant data. We did a claims-database analysis to ascertain the treatment patterns and cost burden of CRSwNP in the USA. We did extensive analyses on the disease using the GALEN sinusitis cohort of patients with chronic rhinosinusitis in Europe. Dupilumab has been shown to have significant efficacy in diseases driven by type 2 inflammation, such as moderate-to-severe atopic dermatitis and moderate-to-severe asthma in patients aged 12 years or older. In a previous phase 2, proof-of-concept study in patients with CRSwNP, dupilumab showed significant efficacy in reducing nasal polyp burden and was well tolerated.
Added value of this study
To our knowledge, LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 are the first and largest phase 3 trials to date assessing a monoclonal antibody targeting this type 2 inflammatory condition, investigating dupilumab efficacy as an add-on treatment to standard intranasal corticosteroids in patients with severe uncontrolled CRSwNP. In both studies, dupilumab reduced nasal polyp size and sinus disease burden, reduced severity of symptoms, improved sense of smell, improved health-related quality of life, and reduced the use of systemic corticosteroids and the need for nasal polyp surgery. In patients with comorbid asthma, dupilumab also improved lung function and asthma control. Dupilumab was shown to be well tolerated.
Implications of all the available evidence
Existing therapies for CRSwNP have limitations and do not address the underlying type 2 inflammatory processes that drive this disease with frequent recurrence. Blocking interleukin (IL)-4 and IL-13 signalling with dupilumab, in addition to the use of intranasal corticosteroids, could improve the lives of patients with severe uncontrolled CRSwNP compared with standard of care. Dupilumab treatment also showed efficacy in treating patients with comorbid asthma, a patient population with an increased disease burden that is difficult to treat.
Dupilumab is a fully human VelocImmune-derived monoclonal antibody18, 19 that inhibits signalling by IL-4 and IL-13, cytokines that are key drivers of type 2 inflammation.20 This antibody has been approved by the US Food and Drug Administration as an add-on maintenance treatment in adult patients with inadequately controlled CRSwNP. Dupilumab has also been approved for the treatment of other type 2 inflammatory disorders, including in patients aged 12 years or older in the USA with moderate-to-severe atopic dermatitis inadequately controlled with topical prescription therapies, or for whom those therapies are not advisable; in adults with inadequately controlled moderate-to-severe atopic dermatitis who are candidates for systemic therapy in the EU and other countries;21, 22, 23 in patients aged 12 years or older in Japan as add-on maintenance treatment for moderate-to-severe asthma with an eosinophilic phenotype, or oral corticosteroid-dependent asthma, and for severe or refractory asthma with symptoms that are inadequately controlled with existing therapy; and in patients with type 2 severe asthma characterised by increased blood eosinophils, raised fractional exhaled nitric oxide, or both, who are inadequately controlled with high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment in the EU.24, 25, 26
In these two phase 3 trials, LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52, we aimed to assess the efficacy and safety of dupilumab when added to standard therapy (intranasal corticosteroids) in adults with severe CRSwNP uncontrolled by standard of care, including patients with a history of comorbid asthma, NSAID-exacerbated respiratory disease, or both.