Laurent Eckert

Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial

BACKGROUND Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count. METHODS We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. FINDINGS 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%). INTERPRETATION Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. FUNDING Sanofi-Genzyme and Regeneron Pharmaceuticals.

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

BACKGROUND Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigators Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING Sanofi and Regeneron Pharmaceuticals Inc.

Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults

BACKGROUND The adult burden of atopic dermatitis (AD) is poorly characterized. OBJECTIVE We sought to characterize AD burden in adults with moderate to severe disease from the patients perspective. METHODS Patient-reported outcomes collected at screening in a phase 2b clinical trial of dupilumab included pruritus numeric rating scale, 5-Dimension Pruritus Scale, subjective components of SCORing AD, Patient-Oriented Eczema Measure, Hospital Anxiety and Depression Scale, Dermatology Life Quality Index, and 5-Dimension EuroQol. RESULTS Most of the 380 patients had been living with AD for nearly all their lives, whereas approximately 40% were given a diagnosis as adults; 40.3% had asthma and 60.5% had other allergic conditions. Despite 48.2% of patients using systemic therapies in the past year, patients reported problems with itch frequency (85% of patients), duration (41.5% reported itching ≥18 h/d), and severity (6.5 of 10 on numeric rating scale); 55% reported AD-related sleep disturbances 5 d/wk or more. Hospital Anxiety and Depression Scale scores suggesting clinically relevant anxiety or depression were reported by 21.8% of patients. Quality of life was impaired on Dermatology Life Quality Index and 5-dimension EuroQol. LIMITATIONS This study had limited generalizability; conclusions may not reflect those with mild AD or not participating in a clinical trial. CONCLUSIONS Adults with moderate to severe AD report multidimensional burden including disease activity, patient-reported symptoms, comorbidities, and quality-of-life impact.

Impact of atopic dermatitis on health-related quality of life and productivity in adults in the United States: An analysis using the National Health and Wellness Survey

Background Given its public health impact, there is need for broad and representative data on the humanistic burden of atopic dermatitis (AD). Objective To establish the humanistic burden of AD in US adults. Methods Data were from the 2013 US National Health and Wellness Survey; AD self‐reports were propensity‐matched with non‐AD controls and with psoriasis controls. Bivariate analyses were conducted on burden outcomes between the AD and control groups. Results Demographics and baseline characteristics were comparable between matched groups. Subjects with AD (n = 349) versus non‐AD controls (n = 698) had significantly higher rates of anxiety, depression, and sleep disorders (29.8%, 31.2%, and 33.2% vs 16.1%, 17.3%, and 19.2%, respectively [all P < .001]); a lower Short Form‐36 v2 mental component summary score (44.5 vs 48.0, respectively [P < .001]); a lower physical component summary score (47.6 vs 49.5, respectively [P = .004]), and lower health utilities (0.67 vs 0.72, respectively [P < .001]) in addition to a higher work absenteeism rate (9.9% vs 3.6%, respectively [P < .001]) and activity impairment rate (33.6% vs 25.2%, respectively [P < .001]). Subjects with AD and psoriasis controls (n = 260 each) showed similar impairment in health‐related quality of life and productivity. Limitations Data were self‐reported. Conclusion AD is associated with a substantial humanistic burden that is similar in magnitude to that of psoriasis, which is also recognized for its debilitating symptoms, indicating the need for more effective treatments for AD.

Dupilumab with concomitant topical corticosteroids in adult patients with atopic dermatitis who are not adequately controlled with or are intolerant to ciclosporin A, or when this treatment is medically inadvisable: a placebo-controlled, randomized phase 3 clinical trial (LIBERTY AD CAFÉ)

Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective in all patients with atopic dermatitis, and side‐effects limit its use. Dupilumab, a fully human anti‐interleukin 4 receptor‐alpha monoclonal antibody, inhibits signaling of IL‐4 and IL‐13, key drivers of Type 2/Th2‐mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately‐controlled moderate‐to‐severe atopic dermatitis in adults.

Epidemiology of atopic dermatitis in adults: Results from an international survey

There are gaps in our knowledge of the prevalence of adult atopic dermatitis (AD).

The burden of atopic dermatitis in US adults: Health care resource utilization data from the 2013 National Health and Wellness Survey

Background: There is a lack of data on the burden of atopic dermatitis (AD) in adults relative to the general population. Objective: To characterize the AD burden in adult patients relative to both matched non‐AD controls and matched patients with psoriasis in terms of comorbidities, health care resource utilization (HCRU), and costs. Methods: Adults (≥18 years) who self‐reported a diagnosis of AD or psoriasis and adult non‐AD controls were identified from the 2013 US National Health and Wellness Survey. Patients with AD were propensity score–matched with non‐AD controls and patients with psoriasis on demographic variables. Patient‐reported outcomes were analyzed between matched cohorts. Results: Patients with AD had a significantly greater risk for atopic comorbidities, as well as significantly greater HCRU and total cost compared with non‐AD controls. The burden of AD was generally comparable to that of psoriasis, although patients with AD reported increased use of emergency room visits compared with patients with psoriasis. Limitations: Patient‐reported data are susceptible to recall bias and erroneous classification. Conclusions: Adult patients with AD reported a substantial disease burden, suggesting an unmet need for more effective AD treatment options.

Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma

Background: Dupilumab, an anti–IL‐4 receptor &agr; mAb, inhibits IL‐4/IL‐13 signaling, key drivers of type 2/TH2 immune diseases (eg, atopic/allergic disease). In a pivotal, phase 2b study (NCT01854047), dupilumab reduced severe exacerbations, improved lung function and quality of life, and was generally well tolerated in patients with uncontrolled persistent asthma despite using medium‐to‐high‐dose inhaled corticosteroids plus long‐acting &bgr;2‐agonists. Objective: To examine dupilumabs effect on the 22‐item Sino‐Nasal Outcome Test (SNOT‐22) total score and its allergic rhinitis (AR)‐associated items in asthma patients with comorbid perennial allergic rhinitis (PAR). Methods: A post hoc analysis reporting data from the phase 2b study for the 200 and 300 mg every 2 week (q2w) doses under investigation in phase 3 (NCT02414854) was carried out. PAR was defined at study entry as a specific response to typical perennial antigens (IgE ≥0.35 Ku/L). Results: Overall, 241 (61%) patients had PAR. In asthma patients with PAR, dupilumab 300 mg q2w versus placebo significantly improved SNOT‐22 total score (least squares mean difference, −5.98; 95% CI, −10.45 to −1.51; P = .009) and all 4 AR‐associated symptoms evaluated (nasal blockage, −0.60; 95% CI, −0.96 to −0.25; runny nose, −0.67; 95% CI, −1.04 to −0.31; sneezing, −0.55; 95% CI, −0.89 to −0.21; postnasal discharge, −0.49; 95% CI, −0.83 to −0.16; all P < .01). Dupilumab 200 mg q2w demonstrated numerical, but not statistically significant, decreases in SNOT‐22 total score (−1.82; 95% CI, −6.46 to 2.83; P = .443 vs placebo) and in each AR‐associated symptom. In patients without PAR, no differences were observed for these measures versus placebo. Conclusions: Dupilumab 300 mg q2w significantly improved AR‐associated nasal symptoms in patients with uncontrolled persistent asthma and comorbid PAR.

Economic evaluation of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults

IntroductionDupilumab significantly improves signs and symptoms of atopic dermatitis (AD), including pruritus, symptoms of anxiety and depression, and health-related quality of life versus placebo in adults with moderate-to-severe AD. Since the cost-effectiveness of dupilumab has not been evaluated, the objective of this analysis was to estimate a value-based price range in which dupilumab would be considered cost-effective compared with supportive care (SC) for treatment of moderate-to-severe AD in an adult population.MethodsA health economic model was developed to evaluate from the US payer perspective the long-term costs and benefits of dupilumab treatment administered every other week (q2w). Dupilumab q2w was compared with SC; robustness of assumptions and results were tested using sensitivity and scenario analyses. Clinical data were derived from the dupilumab LIBERTY AD SOLO trials; healthcare use and cost data were from health insurance claims histories of adult patients with AD. The annual price of maintenance therapy with dupilumab to be considered cost-effective was estimated for decision thresholds of US

Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey

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