Dupilumab in Adults With Moderate to Severe Atopic Dermatitis: A 5-Year Open-Label Extension Study.

Importance: Moderate to severe atopic dermatitis (AD) is a chronic inflammatory skin disease that often requires continuous long-term systemic management. Long-term safety and efficacy data for treatment options are critically important. Objective: To assess the safety and efficacy of dupilumab treatment for up to 5 years in adults with moderate to severe AD. Design, Setting, and Participants: The 5-year LIBERTY AD open-label extension study was conducted from September 2013 to June 2022 at 550 sites in 28 countries. The study enrolled adult patients with moderate to severe AD who had participated in previous dupilumab clinical trials. Data were analyzed from August 2022 to February 2023. Exposures: At enrollment, patients initiated a regimen of subcutaneous dupilumab, 200 mg, weekly (400-mg loading dose). The regimen was amended in June 2014 to dupilumab, 300 mg, weekly (600-mg loading dose) based on a dose-ranging study and again in November 2019 to dupilumab, 300 mg, every 2 weeks to align with the regulatory regimen approvals. Main Outcomes and Measures: The primary end points were the incidence and rate of treatment-emergent adverse events (TEAEs). Key secondary end points included incidence and rate of serious TEAEs and adverse events of special interest, proportion of patients achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear), and proportion of patients with 75% or more improvement in the Eczema Area and Severity Index (EASI) from the parent study baseline. Results: A total of 2677 patients were enrolled and treated in the open-label extension study; 1611 (60.2%) were male, and the mean (SD) age was 39.2 (13.4) years. A total of 334 patients (12.5%) completed treatment up to week 260. The most common reasons for withdrawal were due to regulatory approval of dupilumab in compliance with the study protocol (810 of 1380 [58.7%]), patient withdrawal (248 of 1380 [18.0%]), and adverse events (116 of 1380 [8.4%]). Exposure-adjusted rates of TEAEs were generally stable or declined throughout the study. Common TEAEs (incidence of 5% or greater) included nasopharyngitis, worsening AD, upper respiratory tract infection, conjunctivitis, conjunctivitis allergic, headache, oral herpes, and injection-site reaction. At week 260, 220 of 326 patients (67.5%) achieved an IGA score of 0 or 1 and 288 of 324 (88.9%) achieved 75% or greater improvement in the EASI. The mean (SD) EASI score was 16.39 (14.60) at baseline and 2.75 (5.62) at end of study. Conclusions and Relevance: In this study, there was sustained safety and efficacy of continuous long-term dupilumab treatment for adults with moderate to severe AD.

Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age.

BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).

Dupilumab Improves Health-Related Quality of Life and a Range of Symptoms in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Improvements in symptomatic experience and health-related quality of life (HRQoL) are among the most important treatment benefits in patients with eosinophilic esophagitis (EoE). We assessed the impact of dupilumab treatment on HRQoL, patients' impression of dysphagia, and symptoms beyond dysphagia in adults/adolescents (≥12 years) with EoE in Parts A and B of the LIBERTY EoE TREET (NCT03633617) study. METHODS: The EoE Symptom Questionnaire (EoE-SQ; frequency and severity of non-dysphagia symptoms), EoE Impact Questionnaire (EoE-IQ; impact of EoE on HRQoL), and Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) of dysphagia were used to assess the efficacy of weekly dupilumab 300 mg vs placebo. RESULTS: At Week 24, dupilumab reduced EoE-SQ Frequency (least squares mean difference vs placebo [95% confidence interval] Part A -1.7 [-2.9, -0.5], Part B -1.4 [-2.3, -0.5]; both P<0.01) and EoE-SQ Severity (Part A -2.0 [-3.9, 0.0], P<0.05, Part B -1.5 [-3.0, 0.1], P=0.07) overall scores, and improved scores across all individual items. Improvement in the dupilumab group was clinically meaningful to patients. Dupilumab also meaningfully improved EoE-IQ average scores and improved individual item scores at Week 24, particularly emotional and sleep disturbance. More dupilumab-treated patients reported improvement in the PGIC of dysphagia vs placebo or reported having no symptoms per the PGIS of dysphagia at Week 24. DISCUSSION: Dupilumab reduced the impact of EoE on multiple aspects of HRQoL, patients' impression of dysphagia, and frequency and severity of symptoms beyond dysphagia in adults/adolescents with EoE.

Study Design of a Phase 2/3 Randomized Controlled Trial of Dupilumab in Adults with Bullous Pemphigoid: LIBERTY-BP ADEPT.

BACKGROUND: Bullous pemphigoid (BP) is a rare, autoimmune, blistering skin disease associated with high disease burden, profoundly decreased quality of life and increased morbidity. Emerging evidence supports an important role for type 2 inflammation in disease pathogenesis. Current management relies on topical and/or systemic corticosteroids, non-selective immunosuppressants and antibiotics with anti-inflammatory properties, which are all limited by side effects and toxicities. Therefore, targeted, efficacious and safe therapies are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation. Several reports of patients successfully treated with dupilumab have been published; however, dupilumab has not been formally assessed in a double-blind, placebo-controlled trial. OBJECTIVES: We report the design of LIBERTY-BP ADEPT, a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of dupilumab in adults with BP. METHODS: LIBERTY-BP ADEPT comprises a 35-day screening, 52-week treatment and 12-week follow-up period. Approximately 98 adults aged 18-90 years with moderate-to-severe BP are being enrolled at 51 sites on 4 continents and randomized 1:1 to subcutaneous dupilumab or placebo every 2 weeks. All participants will receive concomitant oral corticosteroids (OCS). PLANNED OUTCOMES: The primary endpoint is the proportion of patients achieving complete remission off steroid therapy at week 36. Key secondary endpoints include total cumulative OCS dose to week 36, percent change and proportion of patients with ≥ 4-point reduction in the weekly average of daily Peak Pruritus Numerical Rating Scale from baseline to week 36 and percent change in Bullous Pemphigoid Area Index score from baseline to week 36. CONCLUSION: The trial results will provide evidence on whether the efficacy and safety of dupilumab support its use as a potential novel treatment approach for BP and will provide new insights into the role of type 2 inflammation in BP pathogenesis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04206553.

Dupilumab demonstrated efficacy and was well tolerated regardless of prior use of swallowed topical corticosteroids in adolescent and adult patients with eosinophilic oesophagitis: a subgroup analysis of the phase 3 LIBERTY EoE TREET study.

OBJECTIVE: To assess the effect of long-term dupilumab on histological, symptomatic and endoscopic aspects of eosinophilic oesophagitis (EoE) in adolescent and adult patients with and without prior use of swallowed topical corticosteroids (STC) or prior inadequate response, intolerance or contraindication to STC. DESIGN: Pre-specified analysis of data from the phase 3 LIBERTY EoE TREET study on patients who received dupilumab 300 mg once a week or placebo for 24 weeks (W24) in parts A and B, and an additional 28 weeks (W52) in part C. Patients were categorised as with/without prior STC use and with/without inadequate/intolerance/contraindication to STC. The proportion of patients achieving ≤6 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score and Histologic Scoring System grade/stage scores were assessed for each subgroup. RESULTS: Regardless of prior STC use, dupilumab increased the proportion of patients achieving ≤6 eos/hpf and improved DSQ score versus placebo at W24, with improvements maintained or improved at W52. The DSQ score and the proportion of patients achieving ≤6 eos/hpf after switching from placebo to dupilumab at W24 were similar to those observed in the dupilumab group at W24, regardless of prior STC use or inadequate/intolerance/contraindication to STC. Improvements in other outcomes with dupilumab were similar in patients with/without prior STC use or inadequate/intolerance/contraindication to STC. CONCLUSION: Dupilumab 300 mg once a week demonstrated efficacy and was well tolerated in patients with EoE regardless of prior STC use or inadequate response, intolerance and/or contraindication to STC. TRIAL REGISTRATION NUMBER: NCT03633617.

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B-C). METHODS: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B-C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. FINDINGS: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B-C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B-C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was -95·9% (95% CI -96·9 to -94·9) in the weekly dupilumab/weekly dupilumab group, -84·2% (-98·3 to -70·2) in the placebo/weekly dupilumab group, -84·8% (-94·3 to -75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -91·2% (-95·9 to -86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was -1·0 point (95% CI -1·1 to -0·9) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was -0·9 points (-1·0 to -0·8) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was -30·3 points (95% CI -34·5 to -26·1) in the weekly dupilumab/weekly dupilumab group, -27·3 points (-32·1 to -22·4) in the placebo/weekly dupilumab group, -20·9% (-25·4 to -16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -23·7% (-29·1 to -18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was -5·4 points (95% CI -6·1 to -4·6) in the weekly dupilumab/weekly dupilumab group, -6·1 points (-7·3 to -4·9) in the placebo/weekly dupilumab group, -5·2% (-6·0 to -4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -4·3% (-5·4 to -3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B-C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). INTERPRETATION: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Efficacy and Safety of Dupilumab in Patients With Erythrodermic Atopic Dermatitis: A Post Hoc Analysis of 6 Randomized Clinical Trials.

Importance: Erythrodermic atopic dermatitis (AD) is a severe AD subtype defined by extensive skin involvement, leading to complications and sometimes hospitalization. Objective: To assess dupilumab's efficacy and safety in patients with erythrodermic AD in clinical trials. Design, Setting, and Participants: This post hoc analysis included patients enrolled in 6 multicenter, multinational, randomized, double-blind, placebo-controlled trials. Patients included in this analysis met erythrodermic AD criteria of 90% or greater body surface area (BSA) affected by AD and Global Individual Sign Score for erythema of 1 or higher. Data analyses for this post hoc analysis were conducted between March 5, 2019, and October 24, 2020. Interventions: Dupilumab once weekly or every 2 weeks, or placebo, either as monotherapy or with concomitant topical corticosteroids (TCS). Main Outcomes and Measures: Efficacy (BSA, Eczema Area and Severity Index [EASI] score, Peak Pruritus Numerical Rating Scale [PP-NRS] score), changes in serum biomarkers (thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase), and safety (incidence of adverse events) at week 16. Data were pooled within each regimen; monotherapy and concomitant TCS results are shown separately. Results: Of 3075 randomized patients, 209 met criteria for erythrodermic AD at baseline, with the median age being 31 and 39 years in the monotherapy and concomitant TCS trials, respectively, similar to the overall populations (34 and 36 years, respectively); 71.3% (n = 97) and 74.0% (n = 54) of patients, respectively, were male (compared with 58.7% and 60.6% in the overall populations). In patients with erythrodermic AD, dupilumab once weekly and every 2 weeks vs placebo significantly improved percentage of BSA affected by AD (least squares mean percent change [SE]) with monotherapy (-42.0% [7.7%] and -39.9% [6.5%] vs -17.2% [11.0%]; P = .03) and concomitant TCS (-63.2% [6.7%] and -56.1% [9.1%] vs -14.5% [7.3%]; P < .001); EASI score with monotherapy (-58.5% [9.0%] and -58.3% [7.9%] vs -22.3% [12.4%]; P = .004 and P = .003, respectively) and concomitant TCS (-78.9% [7.8%] and -70.6% [10.1%] vs 19.3% [8.2%]; P < .001); and PP-NRS score in monotherapy (-45.9% [7.8%] and -33.9% [6.6%] vs -0.6% [9.4%]; P < .001) and concomitant therapy (-53.0% [8.1%] and -55.7% [10.8%] vs -26.0% [8.8%]; P = .006 and P = .01, respectively). Nominally statistically significant improvement was seen as early as week 1 (EASI and PP-NRS scores with monotherapy). Biomarker levels were significantly reduced vs placebo. The most frequent adverse events in dupilumab-treated patients were injection-site reaction, conjunctivitis, and nasopharyngitis. Conclusions and Relevance: In this post hoc analysis of 6 randomized clinical trials, treatment with dupilumab resulted in rapid, sustained improvements in AD signs and symptoms with acceptable safety in patients with erythrodermic AD, similar to those in the trials' overall patient population. Trial Registration: ClinicalTrials.gov Identifiers: NCT01859988, NCT02277743, NCT02277769, NCT03054428, NCT02260986, NCT02755649.

No Increased Risk of Overall Infection in Adults with Moderate-to-Severe Atopic Dermatitis Treated for up to 4 Years with Dupilumab.

INTRODUCTION: Patients with atopic dermatitis (AD) have an increased risk for infections. This open-label extension study, LIBERTY AD OLE, reports the incidence of infections in adults with moderate-to-severe AD treated with dupilumab for up to 4 years. METHODS: We evaluated infections in adults with moderate-to-severe AD treated with dupilumab 300 mg weekly (qw) or every 2 weeks (q2w; approved regimen) for up to 4 years. Topical corticosteroids (TCS) and calcineurin inhibitors (TCI) were permitted. Exposure-adjusted incidence rates (number of patients with at least one event per 100 patient-years [nP/100 PY]) are reported. RESULTS: Overall, 2677 patients were enrolled and treated with dupilumab: 352 (13.1%) completed up to week 204; 226 patients (8.4%) switched from qw to q2w during the trial. Rates of overall infections (71.27 nP/100 PY), serious and/or severe infections (1.39 nP/100 PY), and infections leading to discontinuation (0.34 nP/100 PY) were consistent with a previous 3-year analysis of this study and low compared with 1-year results in adults with AD treated with placebo + TCS. The cumulative number of patients with treatment-emergent serious or severe infections, non-herpetic or herpetic infections, and total skin infections decreased year-over-year. Limitations included open-label study design with no placebo arm; decreasing sample size at later time points due to sponsor decision to close sites following regulatory approval; qw dosing differs from approved q2w dosing; and patients could use TCS/TCI throughout the study, which may have impacted infection rates. CONCLUSIONS: Continuous long-term dupilumab treatment in adults with moderate-to-severe AD is not associated with an increased risk of overall systemic or cutaneous infections. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01949311. Video Abstract INFOGRAPHIC.

Atopic dermatitis is a chronic disease that causes dry skin, skin inflammation, and itching. Patients with atopic dermatitis have an increased risk of bacterial or viral skin infections, which can cause further serious infections in the entire body. This study investigated the rates of infections in adults with moderate-to-severe atopic dermatitis after 204 weeks (almost 4 years) of dupilumab treatment. The patients received 300 mg of dupilumab every week, and a subset of patients switched to the approved dose of 300 mg of dupilumab every 2 weeks. Patients were allowed the use of topical corticosteroids. Among the patients receiving dupilumab for up to 4 years, rates of total infections, serious and severe infections, and infections leading to treatment discontinuation were consistent with a previously published 3-year evaluation. The infection rates in the 4-year study were lower than those in a previous 1-year study in adults with atopic dermatitis treated with placebo and topical corticosteroids. Importantly, our results showed that the cumulative number of patients with total skin infections decreased over 4 years of dupilumab treatment. The number of patients with severe infections appearing after the start of treatment, herpes viral infections, and infections not involving herpes virus also decreased yearly during the 4-year study. The safety data presented here show that long-term dupilumab treatment does not increase the overall risk of skin infections, and provides important evidence related to continuous use of dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis. METHODS: We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). RESULTS: In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [P<0.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C. CONCLUSIONS: Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.).

Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) often requires long-term management with systemic therapies. OBJECTIVE: Our objective was to report the safety and efficacy of dupilumab treatment up to 4 years in adults with moderate-to-severe AD and efficacy in a subgroup of patients who transitioned from dupilumab once-weekly (qw) to administration every other week (q2w). METHODS: This interim analysis of the open-label extension study (NCT01949311) evaluated dupilumab 300 mg qw or q2w in adults previously enrolled in dupilumab trials for moderate-to-severe AD. Patients switched from qw to q2w following protocol amendment. The primary outcome was safety; efficacy was also assessed. RESULTS: Of 2677 patients enrolled and treated, 352 (13.1%) completed week 204 (end of efficacy assessments) and 202 (7.5%) completed safety follow-up through week 244. Self-reported compliance was 98.1%. Dupilumab's safety profile was consistent with previous reports. Common treatment-emergent adverse events (≥5%) included nasopharyngitis, AD, upper respiratory tract infection, oral herpes, conjunctivitis, injection-site reaction, and headache. At week 204, mean ± standard deviation (SD) Eczema Area and Severity Index was 2.46 ± 3.98, and mean percent change from parent study baseline (PSBL) was -91.07%; mean ± SD Pruritus Numerical Rating Scale score was 2.10 ± 1.83, and mean percent change from PSBL was -68.74%. Efficacy was maintained in patients (n = 226) who transitioned from qw to q2w dosing. Limitations of this study included its open-label design, the lack of control arm, and smaller subsets of patients at later timepoints and receiving the approved q2w regimen. CONCLUSION: These results support dupilumab as continuous long-term treatment for adults with moderate-to-severe AD; efficacy was sustained following transition from qw to q2w dosing. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01949311.

Atopic dermatitis is a chronic skin disease associated with inflamed skin and intense itching. People with moderate-to-severe atopic dermatitis often need long-term treatment, but many available treatments do not have demonstrated long-term safety data. In multiple clinical trials, dupilumab treatment resulted in significant improvements in signs and symptoms of atopic dermatitis. This study examined the safety and efficacy of up to 4 years of dupilumab treatment in adults with moderate-to-severe atopic dermatitis, and whether dupilumab continued to be effective in patients who switched from receiving treatment each week to treatment every other week. To address these questions, we collected data from adults who received 300 milligrams of dupilumab every week or every other week. In this study, safety findings were consistent with the known dupilumab safety profile. Patients' signs and symptoms were evaluated before and during treatment with evaluation tools including the Eczema Area and Severity Index (EASI), which indicates the extent and severity of disease, and the Pruritus Numerical Rating Scale (NRS), which indicates the intensity of itching. Reductions of 91% in EASI scores and 69% in Pruritus NRS scores showed that the improvement in signs and symptoms persisted for 204 weeks (almost 4 years) of treatment, and these effects were sustained following the switch from weekly treatment to the approved every other week treatment with dupilumab. The safety and efficacy data presented here support the use of dupilumab as a continuous, long-term treatment for up to 4 years for adults with moderate-to-severe atopic dermatitis. Video abstract: What is the long-term safety and efficacy profile of dupilumab in adults with moderate-to-severeatopic dermatitis for up to 4 years? (MP4 102515 KB).

Variables in Cryosurgery Technique Associated With Clearance of Actinic Keratosis.

BACKGROUND: Cryosurgery is the most commonly used method to treat actinic keratosis (AK). Cryosurgical methods are not standardized. OBJECTIVE: To examine differences in the spray techniques used for liquid nitrogen cryosurgery when treating AKs of the head, and the effect of these variations in technique on rates of complete clearance of AKs. MATERIALS AND METHODS: Patients were those from the FIELD-1 study, who received cryosurgery as per the investigators' usual practice to all AKs. This was followed by topical treatment with either vehicle gel or ingenol mebutate gel, 0.015%, after 3 weeks. The investigator recorded the average duration of cryosurgery spray used, the number of freeze-thaw cycles, and the distance from the tip of the spray device to the AK. Clearance rates were determined at Week 11. RESULTS: Less-aggressive freezing techniques were used for AKs on the face than for those on the scalp. However, higher rates of complete clearance on the face and scalp were associated with more-aggressive freezing techniques. CONCLUSION: Patients with AKs on the face receive less-aggressive cryosurgery than do patients with AKs on the scalp.

Resident Rounds: Part III - Case Report: A Non-Syndromic Case of Multiple Unilateral Nodular and Pigmented Basal Cell Carcinomas.

Although basal cell carcinomas (BCC) are relatively common, particularly in older individuals, the development of multiple BCCs at a young age can indicate an associated genetic disorder. Several cases of unilateral or segmental BCCs have been described in the literature. Some cases have demonstrated concomitant syndromic findings while others had unilateral BCCs as the only finding. Herein we present a non-syndromic case of multiple unilateral nodular and pigmented BCCs in a 61-year-old Hispanic man.

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro.

Although chronic wounds are common and continue to be a major cause of morbidity and mortality, treatments for these conditions are lacking and often ineffective. A large body of evidence exists demonstrating the therapeutic potential of mesenchymal stem cells (MSCs) for repair and regeneration of damaged tissue, including acceleration of cutaneous wound healing. However, the exact mechanisms of wound healing mediated by MSCs are unclear. In this study, we examined the role of MSC exosomes in wound healing. We found that MSC exosomes ranged from 30 to 100-nm in diameter and internalization of MSC exosomes resulted in a dose-dependent enhancement of proliferation and migration of fibroblasts derived from normal donors and chronic wound patients. Uptake of MSC exosomes by human umbilical vein endothelial cells also resulted in dose-dependent increases of tube formation by endothelial cells. MSC exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and induce the expression of a number of growth factors [hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)]. These findings represent a promising opportunity to gain insight into how MSCs may mediate wound healing.

Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing.

INTRODUCTION: Recent evidence has shown that bone marrow cells play critical roles during the inflammatory, proliferative and remodeling phases of cutaneous wound healing. Among the bone marrow cells delivered to wounds are stem cells, which can differentiate into multiple tissue-forming cell lineages to effect, healing. Gaining insight into which lineages are most important in accelerating wound healing would be quite valuable in designing therapeutic approaches for difficult to heal wounds. METHODS: In this report we compared the effect of different bone marrow preparations on established in vitro wound healing assays. The preparations examined were whole bone marrow (WBM), whole bone marrow (long term initiating/hematopoietic based) cultured cells (BMC), and bone marrow derived mesenchymal stem cells (BM-MSC). We also applied these bone marrow preparations in two murine models of radiation induced delayed wound healing to determine which had a greater effect on healing. RESULTS: Angiogenesis assays demonstrated that tube formation was stimulated by both WBM and BMC, with WBM having the greatest effect. Scratch wound assays showed higher fibroblast migration at 24, 48, and 72 hours in presence of WBM as compared to BM-MSC. WBM also appeared to stimulate a greater healing response than BMC and BM-MSC in a radiation induced delayed wound healing animal model. CONCLUSIONS: These studies promise to help elucidate the role of stem cells during repair of chronic wounds and reveal which cells present in bone marrow might contribute most to the wound healing process.