Summary 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 Investigator's 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.
Background
Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared ...receptor component for interleukin‐4 and interleukin‐13, key and central drivers of type 2 inflammation.
Objective
Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE).
Methods
Data were extracted from three randomized placebo‐controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation‐regulated chemokine (TARC), plasma eotaxin‐3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count.
Results
Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin‐3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from −24.8% to −88.6% (placebo +2.6% to −53.6%); −38.2% to −51.5% (placebo +8.3% to −0.16%) in eotaxin‐3; −24.8% to −76.7% (placebo +8.3% to −4.4%) in total IgE; and −13.6% to −41.1% (placebo +10.1% to −6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% 95% CI: −15.8, 0); transient increases followed by decreases to below‐baseline levels in asthma (−14.6% −20.0, −7.7) and CRSwNP (−29.4% −40.0, −16.3); and significant decreases in EoE (−50.0% −50.0, −33.3).
Conclusion and clinical relevance
Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.
This analysis assessed dupilumab effect on biomarkers of type 2 inflammation in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. Dupilumab vs. placebo suppressed thymus and activation‐regulated chemokine, total immunoglobulin E, periostin, and eotaxin‐3 in all studies/indications where assessed; blood eosinophil responses varied by disease. Dupilumab may affect a shared pathophysiological mechanism fundamental to type 2 inflammatory diseases.
In young children, atopic dermatitis (AD) imposes a multidimensional burden on many aspects of their quality of life (QoL) and that of their families. LIBERTY AD PRESCHOOL part B was a randomized, ...double- blinded, placebo-controlled phase 3 trial in 162 children (aged 6 months to 5 years) with moderate-to- severe AD receiving dupilumab or placebo, plus low-potency topical corticosteroids. Post hoc analyses were performed on the full analysis set (FAS) and a subset of patients with Investigator's Global Assessment score > 1 at week 16. The primary outcome was the proportion of patients at week 16 achieving a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms and QoL: ≥ 50% improvement in Eczema Area and Severity Index; and/or ≥ 4-point reduction in worst scratch/itch numerical rating scale; and/or ≥ 6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients receiving dupilumab vs placebo achieved the composite endpoint in both the FAS (77.7% vs 24.6%, p < 0.0001) and subgroup (68.9% vs 21.5%, p < 0.0001). Dupilumab provided rapid and significant, clinically meaningful improvements in AD signs, symptoms, and QoL in the overall group and subgroup of patients who did not achieve clear or almost clear skin at week 16.
Most systemic agents used for moderate-to-severe atopic dermatitis (AD) may lead to adverse events requiring routine laboratory monitoring, increasing patient burden and possibly decreasing treatment ...adherence.
To evaluate clinical laboratory findings in adults with moderate-to-severe AD treated with dupilumab up to 3 years.
LIBERTY AD OLE (NCT01949311) was a phase 3, multicenter, open-label extension study in adults with moderate-to-severe AD receiving dupilumab 300 mg weekly.
2,677 patients were treated up to 3 years. No clinically meaningful changes in mean hematology/serum chemistry parameters from baseline were observed. Few laboratory abnormalities were reported as treatment-emergent adverse events. Serious events included one event each of thrombocytopenia, hematuria, and hemolytic anemia, all unrelated to treatment. Abnormalities leading to treatment withdrawal included thrombocytopenia (one patient), increased hepatic enzymes (two patients), and blood creatine phosphokinase increased (one patient). No patients had Grade 3 anemia or Grade 3/4 thrombocytopenia; one patient had Grade 3 neutropenia (Week 100); two patients had Grade 3 eosinophilia (baseline visit); no eosinophil abnormalities were associated with clinically symptomatic events/permanent treatment discontinuation.
Dupilumab treatment of adults with moderate-to-severe AD up to 3 years showed no clinically meaningful changes in mean laboratory parameters, supporting continuous long-term use without laboratory monitoring.
NCT01949311
Optimal management of atopic dermatitis requires a comprehensive assessment of response to treatment in order to inform therapeutic decisions. In a real-world setting, successful response to atopic ...dermatitis treatment is measured by sustained improvements in signs, symptoms, and quality of life. Post-hoc analyses of a 1-year, randomized, double-blinded, placebo- controlled trial (NCT02260986) of dupilumab with concomitant topical corticosteroids in 421 adults with moderate-to-severe atopic dermatitis (of whom 315/106 received placebo/dupilumab (of whom 315 received placebo and 106 received dupilumab) was performed to assess the proportion of responders to dupilumab through a multidimensional composite endpoint. At 6-months, 80.2% of dupilumab-treated vs 40.0% placebo patients (p < 0.0001) achieved improvement in signs (Eczema Area and Severity Index ≤ 7), symptoms (worst itch score ≤ 4), or quality of life (Dermatology Life Quality Index ≤5), representative of minimal/clear atopic dermatitis. All 3 endpoints, indicative of no/minimal atopic dermatitis, were achieved by 44.3% of dupilumab-treated vs 10.2% placebo patients (p < 0.0001) and sustained through 1 year. Dupilumab treatment provided sustained clinically meaningful improvement in signs, symptoms, and quality of life in adults with moderate-to-severe atopic dermatitis.
Introduction
Atopic dermatitis (AD) can require long-term therapy. Few real-world studies have evaluated long-term effectiveness from the patients’ perspective. The aim of this study was to evaluate ...patient-reported outcomes (PROs) during long-term dupilumab treatment.
Methods
Adults with moderate-to-severe AD who initiated dupilumab through the US manufacturer patient support program and participated in RELIEVE-AD (a prospective patient survey study with a 12-month follow-up) were recontacted 30–36 months post-initiation regardless of current dupilumab use. The online questionnaire consisted of PROs, including the Atopic Dermatitis Control Tool (ADCT), use of concomitant AD therapies, satisfaction with current therapy, global change in itch relative to before dupilumab initiation, non-itch skin symptoms (skin pain/soreness, hot/burning feeling, and sensitivity to touch), flares, Dermatology Life Quality Index, sleep problems, and the AD-specific Work Productivity and Activity Impairment Questionnaire.
Results
Of 698 patients who initiated dupilumab (baseline) and were recontacted, 425 completed the 30–36-month survey. Significant reductions from baseline were reported in concomitant AD therapy use (
P
< 0.05); 54.4% reported not using other AD medications vs. 12.8% at baseline. At 30–36 months, all results (non-itch skin symptoms, flares, sleep problems, health-related quality of life work/activity impairment, disease control, and treatment satisfaction) were similar to or incrementally better than the 12-month timepoint, with significant improvements vs. baseline (
P
< 0.001). Global change in itch was reported as “very much better” by 75.3% of respondents. Adequate disease control (score < 7 on ADCT) was reported by 80.7% of respondents, and 86.8% were satisfied with the treatment.
Conclusions
In clinical practice settings, patient-reported benefits of dupilumab were maintained in survey respondents during long-term treatment up to 36 months while the use of concomitant AD therapies reduced.
Plain Language Summary
Atopic dermatitis (also known as eczema) is a chronic skin disease that can have a profoundly negative effect on patients’ quality of life. To control disease symptoms, patients often need long-term treatment. Dupilumab is a treatment that has shown benefits in adults with moderate-to-severe atopic dermatitis (AD) when used in long-term (under 4 years) clinical trials; however, few studies have evaluated patients’ experiences of long-term dupilumab treatment outside of a clinical trial setting. This study was conducted to do so: 425 adults with moderate-to-severe AD who received dupilumab through a US manufacturer patient support program filled in an online questionnaire 30–36 months after starting treatment. The questionnaire included items on use of additional AD therapies, AD symptoms, quality of life, disease control, and satisfaction with treatment. Patients’ responses showed that, at 30–36 months after starting dupilumab treatment, 54% of patients reported not using any other medications for AD vs. 13% of patients when starting dupilumab treatment. In addition, since starting dupilumab, 75% of patients reported one of the most burdensome AD symptoms, itch, as being “very much better” vs. before starting treatment; 81% reported control of AD symptoms; 85% reported a meaningful improvement in quality of life; and 76% were “extremely” or “very” satisfied with the treatment. In summary, this study showed that long-term dupilumab treatment provides continued improvement in symptoms, treatment satisfaction, disease control, and quality of life in adults with moderate-to-severe AD while reducing the need for other AD treatments.
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Video abstract: How do patients with atopic dermatitis perceive long-term dupilumab treatment in the real world? (MP4 31888 kb)
Introduction
Patients with atopic dermatitis (AD) have a greater risk of conjunctivitis and other ocular surface disorders than the general population. We evaluated the burden of ocular surface ...disorders and related symptoms prior to treatment initiation in adults with moderate-to-severe AD.
Methods
Patients were enrolled in a randomized, placebo-controlled, double-blinded, phase 3 trial of dupilumab administered with concomitant topical corticosteroids. At the beginning of the screening period, all enrolled patients completed a survey of ocular disorder diagnoses received in the past year; at baseline, patients completed a survey of frequency and severity of ocular symptoms (discomfort, itching, redness, and tearing) experienced in the past month.
Results
A total of 712 of 740 patients enrolled in the trial provided responses to the survey. At screening, 286 of 740 patients (38.6%) reported having at least one ocular disorder in the past year. At baseline, 499 of 712 respondents (70.1%) reported having at least one symptom within the past month. Of these patients, 4.4%, 6.0%, 5.5%, and 4.4%, respectively, reported having discomfort, itching, redness, and tearing all of the time. Mild discomfort, itching, redness, and tearing were reported by 26.1%, 33.7%, 30.8%, and 31.6% of patients, respectively, while 7.3%, 7.7%, 6.2%, and 4.2%, reported severe discomfort, itching, redness, and tearing, respectively.
Conclusions
These data demonstrate a high burden of ocular surface disorders and related symptoms in a population of adults with moderate-to-severe AD. Dermatologists should be aware of increased incidence of these disorders in AD and query their patients for signs and symptoms of eye disease.
ClinicalTrials.gov Registration Number
NCT02260986.
Background
Treatment responses may differ between patients with severe versus moderate atopic dermatitis (AD).
Objectives
To assess dupilumab response by baseline AD severity in adolescent and adult ...patients with moderate‐to‐severe AD.
Methods
We assessed dupilumab response by baseline AD severity in 1719 patients aged ≥12 years with moderate‐to‐severe AD from five randomized, double‐blind, placebo‐controlled trials. Patients received subcutaneous placebo or dupilumab as monotherapy (300 mg adults, adolescents or 200 mg adolescents every 2 weeks; 16 weeks), or with concomitant topical corticosteroids (TCS) (adults; 16/52 weeks). Patients were stratified by baseline Investigator's Global Assessment (IGA) score (3 moderate/4 severe).
Results
Dupilumab‐treated patients with moderate AD had numerically higher absolute proportions of patients achieving IGA 0/1 (clear/almost clear) than those with severe AD; risk differences (dupilumab vs. placebo) were 18.9–35.5 for moderate AD and 16.4–34.2 for severe AD. For all other endpoints assessed, no meaningful differences or consistent response patterns between moderate and severe subgroups were observed.
Conclusions
Dupilumab with or without TCS demonstrated similar efficacy in patients with moderate or severe AD.
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