Dupilumab Efficacy in Patients with Type 2 Asthma with and without Elevated Blood Neutrophils.

Introduction: Elevated neutrophil counts in blood, sputum, or lung have been associated with poor clinical outcomes and more severe disease in patients with type 2 asthma. In the phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks compared with matched placebo significantly reduced severe asthma exacerbations and improved forced expiratory volume in 1 s (FEV1) in patients with uncontrolled, moderate-to-severe asthma. This post hoc analysis explored the efficacy of dupilumab in patients with type 2 asthma enrolled in QUEST with or without elevated blood neutrophil counts. Methods: Annualized severe exacerbation rates during the 52-week treatment period and least-squares mean change from baseline in FEV1 over time were evaluated for patients with elevated type 2 biomarkers at baseline (blood eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 20 ppb; and eosinophils ≥ 300 cells/µL or FeNO ≥ 50 ppb) and low (<4,000 cells/µL) or high (≥4,000 cells/µL) neutrophil counts. Results: Dupilumab significantly reduced annualized severe exacerbation rates compared with placebo during the 52-week treatment period in patients with elevated type 2 biomarkers, irrespective of baseline neutrophil count (P < 0.0001 for all comparisons). Significant improvements in FEV1 versus placebo were observed as early as Week 2 and over the 52-week treatment period, irrespective of baseline neutrophil count (P < 0.001 for all comparisons). Safety findings were similar across all subgroups, regardless of neutrophil counts at baseline. Conclusions: Dupilumab treatment significantly reduced annualized severe exacerbation rates and improved lung function in patients with uncontrolled, moderate-to-severe, type 2 asthma, irrespective of baseline blood neutrophil count. This trial is registered with NCT02414854.

Dupilumab Efficacy in Patients with Uncontrolled Moderate-to-Severe Type 2 Asthma Regardless of Perennial Aeroallergen Sensitization.

Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 (T2) inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), dupilumab vs placebo significantly reduced asthma exacerbation rates (AER) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater effects in patients with elevated T2 biomarkers (≥150 eosinophils/µL or fractional exhaled nitric oxide [FeNO] ≥25 parts per billion). Overall safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed dupilumab efficacy in QUEST patients with T2 asthma with evidence of an allergic phenotype (baseline serum IgE ≥30 IU/mL and aeroallergen-specific IgE ≥0.35 IU/mL) by number of aeroallergen sensitizations: 1, 2, 3, or ≥4. Non-sensitized patients (serum total IgE <30 IU/mL without evidence of allergic phenotype) were also assessed. Patients and Methods: Endpoints were annualized AER, change from baseline in pre-bronchodilator FEV1 and asthma control (5-item Asthma Control Questionnaire [ACQ-5]), and FeNO and serum total IgE levels over the 52-week treatment period. Results: In all subgroups by number of allergens sensitized, dupilumab vs placebo reduced AER by 35-67% and improved both pre-bronchodilator FEV1 at Week 12 (least squares mean differences: 0.10-0.26 L across subgroups) and ACQ-5 score at Week 52 (-0.26 to -0.43). Dupilumab significantly reduced FeNO and total IgE levels at Week 52 compared with placebo. Similar results were observed in non-sensitized patients. Conclusion: Dupilumab improved clinical outcomes and reduced biomarker levels in patients with uncontrolled, moderate-to-severe T2 asthma irrespective of allergen sensitization status or number. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02414854.

The long-term effect of dupilumab on dyspnea, sleep, and activity in oral corticosteroid-dependent severe asthma.

BACKGROUND: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction. METHODS: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE. RESULTS: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively. CONCLUSION: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028.