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.

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. 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. 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. 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. Sanofi and Regeneron Pharmaceuticals.

Bachert C ，Han JK ，Desrosiers M ，Hellings PW ，Amin N ，Lee SE ，Mullol J ，Greos LS ，Bosso JV ，Laidlaw TM ，Cervin AU ，Maspero JF ，Hopkins C ，Olze H ，Canonica GW ，Paggiaro P ，Cho SH ，Fokkens WJ ，Fujieda S ，Zhang M ，Lu X ，Fan C ，Draikiwicz S ，Kamat SA ，Khan A ，Pirozzi G ，Patel N ，Graham NMH ，Ruddy M ，Staudinger H ，Weinreich D ，Stahl N ，Yancopoulos GD ，Mannent LP ... -  《-》

Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma.

Chronic rhinosinusitis with nasal polyps (CRSwNP) and type 2 asthma share the same inflammatory pathophysiology and are frequent comorbidities. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin 4 and interleukin 13, which are key and central drivers of type 2 inflammation. We report the effect of dupilumab vs placebo on outcome measures of the upper and lower airways and health-related quality of life (HRQoL) in the pooled population of patients with CRSwNP and comorbid asthma from the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies. In these randomized, double-blind, placebo-controlled trials, patients received subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks on a background of mometasone furoate nasal spray. Changes from baseline at week 24 in the upper and lower airway outcome measures are reported. Of the 724 patients randomized, 428 (59.1%) had comorbid asthma. In patients with asthma at week 24, dupilumab vs placebo improved the nasal polyp score (-2.04), patient-reported nasal congestion score (-1.04), Lund-Mackay computed tomography scan score (-6.43), peak nasal inspiratory flow (46.15 L/min), and 22-item sinonasal outcome test score (-21.42; all P < .001). The forced expiratory volume in 1 second and 6-item asthma control questionnaire scores were also markedly improved with dupilumab vs placebo. The most common adverse events (nasopharyngitis, headache, injection-site erythema, worsening of nasal polyposis, and asthma) were more frequent with placebo than dupilumab. Dupilumab improved upper and lower airway outcome measures and HRQoL in patients with severe CRSwNP and comorbid asthma and was well tolerated. ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52).

Laidlaw TM ，Bachert C ，Amin N ，Desrosiers M ，Hellings PW ，Mullol J ，Maspero JF ，Gevaert P ，Zhang M ，Mao X ，Khan AH ，Kamat S ，Patel N ，Graham NMH ，Ruddy M ，Staudinger H ，Mannent LP ... -  《-》

The Effect of Dupilumab on Intractable Chronic Rhinosinusitis with Nasal Polyps in Japan.

Dupilumab, which blocks the shared receptor component for interleukin-4 and interleukin-13, reduced polyp size, sinus opacification, and symptom severity, and was well tolerated in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-52 study (NCT02898454). We assessed dupilumab in patients enrolled at Japanese centers. Patients on a background of mometasone furoate nasal spray, received dupilumab 300 mg every 2 weeks (q2w) for 52 weeks (Arm A); dupilumab 300 mg q2w for 24 weeks, followed by every 4 weeks (q4w) for 28 weeks (Arm B); or placebo (Arm C). Co-primary endpoints were week 24 nasal polyp score (NPS), nasal congestion (NC) score, and sinus Lund-Mackay CT (LMK-CT) scores. Symptoms, sense of smell, health-related quality of life, and safety were assessed during the 52-week treatment period. Of 49 patients enrolled in Japan, 45 completed the study. Week 24 least squares (LS) mean improvement versus placebo were as follows: NPS (Arm A: -3.1, P < .0001; Arm B: -2.1, P = .0011); NC score (Arm A: -1.2, P < .0001; Arm B: -0.9, P < .0001); and LMK-CT (Arm A: -5.1, P = .0005; Arm B: -2.8, P = .0425). The most common treatment-emergent adverse event in dupilumab and placebo-treated patients was nasopharyngitis. Dupilumab provided rapid, significant, and clinically meaningful improvements for patients with CRSwNP in Japan. Dupilumab was well tolerated, and safety and efficacy were consistent with the overall study population. 2 Laryngoscope, 131:E1770-E1777, 2021.

Fujieda S ，Matsune S ，Takeno S ，Asako M ，Takeuchi M ，Fujita H ，Takahashi Y ，Amin N ，Deniz Y ，Rowe P ，Mannent L ... -  《-》

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

Bachert C ，Mannent L ，Naclerio RM ，Mullol J ，Ferguson BJ ，Gevaert P ，Hellings P ，Jiao L ，Wang L ，Evans RR ，Pirozzi G ，Graham NM ，Swanson B ，Hamilton JD ，Radin A ，Gandhi NA ，Stahl N ，Yancopoulos GD ，Sutherland ER ... -  《-》

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.

Blauvelt A ，de Bruin-Weller M ，Gooderham M ，Cather JC ，Weisman J ，Pariser D ，Simpson EL ，Papp KA ，Hong HC ，Rubel D ，Foley P ，Prens E ，Griffiths CEM ，Etoh T ，Pinto PH ，Pujol RM ，Szepietowski JC ，Ettler K ，Kemény L ，Zhu X ，Akinlade B ，Hultsch T ，Mastey V ，Gadkari A ，Eckert L ，Amin N ，Graham NMH ，Pirozzi G ，Stahl N ，Yancopoulos GD ，Shumel B ... -  《-》