Elsevier

The Lancet

Volume 394, Issue 10209, 2–8 November 2019, Pages 1638-1650
The Lancet

Articles
Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials

https://doi.org/10.1016/S0140-6736(19)31881-1Get rights and content

Summary

Background

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.

Methods

LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454.

Findings

Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was −2·06 (95% CI −2·43 to −1·69; p<0·0001) in SINUS-24 and −1·80 (−2·10 to −1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was −0·89 (−1·07 to −0·71; p<0·0001) in SINUS-24 and −0·87 (−1·03 to −0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was −7·44 (−8·35 to −6·53; p<0·0001) in SINUS-24 and −5·13 (−5·80 to −4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo.

Interpretation

In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options.

Funding

Sanofi and Regeneron Pharmaceuticals.

Introduction

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.

Section snippets

Study design

LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing the efficacy and safety of dupilumab in patients with severe uncontrolled CRSwNP. SINUS-24 was done in 67 hospitals or clinical centres in 13 countries (Bulgaria, Czechia, France, Germany, Hungary, Italy, the Netherlands, Poland, Romania, Ukraine, Russia, the UK, and the USA). SINUS-52 was done in 117 hospitals or clinical centres in 14

Results

Between Dec 5, 2016, and Aug 3, 2017, patients were enrolled in SINUS-24, with 276 patients randomly assigned to dupilumab every 2 weeks (n=143) or placebo (n=133; figure 1). The final patient treatment was done on July 5, 2018. Between Nov 28, 2016, and Aug 28, 2017, patients were enrolled in SINUS-52, with 448 patients randomly assigned to placebo (n=153), dupilumab every 2 weeks (n=150), or dupilumab every 2 weeks until week 24 and every 4 weeks until week 52 (n=145; figure 1). The final

Discussion

Patients with CRSwNP generally have a high symptom burden, including anosmia, high polyp recurrence rates, asthma comorbidity, and poor health-related quality of life. In patients with severe CRSwNP inadequately controlled with standard of care, adding dupilumab to daily MFNS provided early, significant, and clinically meaningful improvements across all aspects of disease, including a reduction in systemic corticosteroid treatment and surgery. This broad and significant effect was reflected in

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