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Background: Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6–17 years) with moderate‐to‐severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk–benefit profile in younger children remains a significant unmet need. Objectives: To determine the pharmacokinetics, safety and efficacy of single‐dose dupilumab in children with severe AD aged ≥6 months to <6 years. Methods: This open‐label, multicenter, phase 2, sequential, two‐age cohort, two‐dose level study (LIBERTY AD PRE‐SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4‐week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low‐to‐medium potency topical corticosteroids was allowed. Results: Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose‐proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by −44.6% and −49.7% (older cohort) and −42.7% and −38.8% (younger cohort), and mean Peak Pruritus NRS scores by −22.9% and −44.7% (older cohort) and −11.1% and −18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. Conclusions: Single‐dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non‐linear, consistent with previous studies in adults and adolescents. [ABSTRACT FROM AUTHOR]

Sleep disturbances are part of a symptom triad, along with itch and pain, that patients with atopic dermatitis (AD) report as being frequent and burdensome.1 The effects of dupilumab on sleep were evaluated in adults with chronic AD in five randomized, double-blind, placebo-controlled clinical trials ( I N i = 2632). 2a), sleep disturbances were reported to be less frequent among dupilumab-treated patients vs. placebo-treated patients; in particular, 58.6-63.4% of dupilumab-treated patients vs. 40.5% of placebo-treated patients reported no days of sleep disturbances. [Extracted from the article]

Summary: Background: Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate‐to‐severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate‐to‐severe AD inadequately controlled with topical medications. Objectives: To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double‐blinded, placebo‐controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). Methods: Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. Results: Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab‐treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab‐treated and placebo‐treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. Conclusions: There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate‐to‐severe AD that does not require laboratory monitoring. What's already known about this topic? Long‐term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side‐effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities.Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)‐4 and IL‐13] is approved for the treatment of patients with inadequately controlled, moderate‐to‐severe AD.In 16‐week and 52‐week studies, dupilumab demonstrated a positive risk/benefit profile in moderate‐to‐severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16‐week SOLO 1 & 2 (pooled N = 1376) and 52‐week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate‐to‐severe AD treated with dupilumab.Our data support the use of dupilumab as a systemic treatment for the long‐term management of moderate‐to‐severe AD without routine laboratory monitoring in clinical practice. Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Background: Dupilumab (monoclonal antibody inhibiting IL‐4/IL‐13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate‐to‐severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16‐week, randomised, placebo‐controlled phase III trial in adolescents (NCT03054428). Objectives: To characterize the pharmacokinetics of dupilumab, and long‐term safety and efficacy in adolescents. Methods: This was a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study with a phase III open‐label extension (OLE) in adolescents with moderate‐to‐severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg−1 or 4 mg kg−1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8‐week safety follow‐up. Patients then enrolled in the OLE, continuing 2 mg kg−1 or 4 mg kg−1 dupilumab weekly. Primary end points were dupilumab concentration–time profile and incidence of treatment‐emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). Results: Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target‐mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L−1 and 161 ± 60 mg L−1 for 2 mg kg−1 and 4 mg kg−1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg−1], 47% [4 mg kg−1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction −34% ± 20% (2 mg kg−1) and −51% ± 29% (4 mg kg−1)]. With continuing treatment, EASI scores improved further [week 52: −85% ± 12% (2 mg kg−1) and −84% ± 20% (4 mg kg−1)]. Conclusions: In adolescents with moderate‐to‐severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52‐week safety and efficacy data support long‐term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate‐to‐severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options.Dupilumab (monoclonal antibody against interleukin‐4 receptor α) is approved for the treatment of adolescents with moderate‐to‐severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union).A 16‐week, randomized, placebo‐controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long‐term safety and efficacy of dupilumab in adolescents with moderate‐to‐severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16‐week dupilumab phase III trial.The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16‐week phase III monotherapy trial. Linked Comment: Sibbald. Br J Dermatol 2020; 182:12–13. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Moderate‐to‐severe atopic dermatitis (AD) is a chronic disease characterized by intense, persistent and debilitating itch, resulting in sleep deprivation, signs of anxiety and depression, impaired quality of life and reduced productivity. The Peak Pruritus Numerical Rating Scale (NRS) was developed and validated as a single‐item, patient‐reported outcome (PRO) of itch severity. Objectives: To describe the content validity and psychometric assessment (test–retest reliability, construct validity, known‐groups validity, sensitivity to change) of the Peak Pruritus NRS, and to derive empirically a responder definition to identify adults with a meaningful change in itch. Methods: Content validity was assessed through in‐depth patient interviews. Psychometric assessments used data from phase IIb and phase III dupilumab clinical trials and included test–retest reliability, construct validity, known‐groups validity and sensitivity to change in patients with moderate‐to‐severe AD. Results: Interview participants indicated that the Peak Pruritus NRS was a relevant, clear and comprehensive assessment of itch severity. Peak Pruritus NRS scores showed large, positive correlations with existing PRO measures of itch, and weak or moderate correlations with clinician‐reported measures assessing objective signs of AD. Peak Pruritus NRS score improvements were highly correlated with improvements in other itch PROs, and moderately correlated with improvements in clinician‐reported measures assessing objective signs of AD. The most appropriate threshold for defining a clinically relevant, within‐person response was ≥ 2–4‐point change in the Peak Pruritus NRS. Conclusions: The Peak Pruritus NRS is a well‐defined, reliable, sensitive and valid scale for evaluating worst itch intensity in adults with moderate‐to‐severe AD. What's already known about this topic? Moderate‐to‐severe atopic dermatitis is characterized by persistent and debilitating itch, which can greatly impair quality of life.A validated, brief patient‐reported outcome measure is needed to quantify the intensity of itch accurately and reliably in patients with atopic dermatitis in clinical trials. What does this study add? The Peak Pruritus Numerical Rating Scale (NRS) is a well‐defined, reliable, fit‐for‐purpose measure to evaluate patient‐reported intensity of worst itch in the previous 24 h for adults with moderate‐to‐severe atopic dermatitis.Clinical response is indicated by a ≥ 2–4‐point change from baseline in Peak Pruritus NRS score. What are the clinical implications of this work? This study provides practising clinicians and clinical trialists with a validated patient‐reported outcome measure to assess itch, a hallmark symptom of atopic dermatitis and a crucial marker of treatment benefit. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Background: In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab. Objectives: To evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life. Methods: LIBERTY AD SOLO 1 and 2 were two 16‐week, randomized, double‐blind trials enrolling adult patients with moderate‐to‐severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient‐Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769. Results: At week 16, 278 of 449 dupilumab q2w‐treated patients (median age 36·0 years) and 396 of 443 placebo‐treated patients had IGA > 1. Among patients with IGA > 1 at week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (−48·9% vs. −11·3%, P < 0·001), pruritus NRS (−35·2% vs. −9·1%, P < 0·001), affected BSA (−23·1% vs. −4·5%, P < 0·001), POEM score ≥ 4‐point improvement (57·4% vs. 21·0%, P < 0·001) and DLQI score ≥ 4‐point improvement (59·3% vs. 24·4%, P < 0·001). Conclusions: In patients with IGA > 1 at week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant dupilumab treatment effects. What's already known about this topic? An Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin) is considered the regulatory standard for treatment success in trials of patients with atopic dermatitis in the U.S.A.It is currently unknown whether patients receiving dupilumab treatment for moderate‐to‐severe atopic dermatitis derive clinical and quality‐of‐life benefit even if they have an end‐of‐treatment IGA score > 1. What's does this study add? This post hoc analysis of patients with an end‐of‐treatment IGA score > 1 from two randomized, placebo‐controlled trials showed that after 16 weeks of treatment dupilumab significantly improved their outcome measures compared with placebo, including measures of signs, symptoms and quality of life.These results show that the regulatory IGA ≤ 1 end point used in clinical trials significantly underestimates clinically relevant dupilumab treatment effects, underscoring potential limitations of the IGA scale. Linked Comment: de Bruin‐Weller. Br J Dermatol 2019; 181:12–13. Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Atopic dermatitis (also known as AD or eczema) is a common skin disease that can cause intense and persistent itching and rashes. Skin creams or ointments are not suitable or effective for some patients with moderate‐to‐severe AD. In these patients, oral (taken by mouth) or injected medications may be required. Some of those oral or injected treatments could be toxic and often have unwanted side effects, especially when used for a longer period of time, so patients must be regularly tested to see whether those treatments are harming their blood or organs. Dupilumab is a newer injectable drug for treating moderate‐to‐severe AD. Dupilumab specifically targets key molecules in the body that cause AD. Dupilumab has been tested for up to one year in more than 2000 patients enroled in placebo‐controlled clinical trials. During those trials, patients provided blood and urine samples for laboratory testing while they were being treated with dupilumab or placebo (dummy drug). In this paper, the authors from Germany and the U.S.A, analysed how blood cells, blood chemistry, and urine chemistry changed during treatment, to check whether dupilumab is safe to use without the need for regular laboratory tests. After performing many routine laboratory tests on patients' blood and urine, they found that there were no clinically important changes in test results that could be linked to dupilumab. They concluded that patients using dupilumab for moderate‐to‐severe AD do not need routine laboratory testing. This is a summary of the study: Laboratory safety of dupilumab in moderate‐to‐severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS) Linked Article: Wollenberg et al. Br J Dermatol 2020; 182:1120–1135 [ABSTRACT FROM AUTHOR]

Summary: Atopic dermatitis (AD), also known as eczema, is characterized by red, oozy, and dry skin that can become cracked and infected. Intense itching, which can be very troublesome and can cause sleep disturbance, is the main complaint of patients with AD. AD often begins in childhood and affects 1 in 4 teenagers worldwide. For teenagers, the itchiness and appearance of AD skin can significantly reduce quality of life, but there are few effective treatment options for moderate‐to‐severe AD that are suitable for long‐term use. Dupilumab is a new drug that blocks key molecules that cause allergic conditions, such as AD. It has been shown to be effective in treating moderate‐to‐severe AD in adults and to be relatively safe for long‐term use. This study was conducted in multiple centres across Europe and Canada in 40 patients aged 12 to 17 who received treatment with dupilumab for up to a year. The researchers wanted to know whether dupilumab is effective and safe for treating AD with long‐term use in these patients. They also wanted to know how dupilumab is processed by the body in patients with AD in this age group. They found that treatment with dupilumab substantially improves the skin and symptoms of AD, including itching, in these younger patients, without causing any unexpected side effects. They also found that dupilumab is processed the same way in these younger patients as in adults. The improvements were maintained throughout the one year of treatment. The study results support the use of dupilumab in the continuous treatment of adolescents with moderate‐to‐severe AD. This summary relates to the study: Dupilumab in adolescents with uncontrolled moderate‐to‐severe atopic dermatitis: results from a phase IIa open‐label trial and subsequent phase III open‐label extension Linked Article: Cork et al. Br J Dermatol 2020; 182:85–96 [ABSTRACT FROM AUTHOR]

Summary: Atopic dermatitis (AD) is a chronic skin disease occurring in about 5 to 10% of adults worldwide. It can cause intense and persistent itch. For almost two‐thirds of patients with moderate‐to‐severe AD, the itching lasts at least 12 hours a day, and is severe to unbearable. In clinical trials that are looking at how effective a treatment for AD is, itch intensity must be measured. Given itch is subjective, its intensity is most accurately reported by patients themselves. In this study, investigators from the U.S.A. and Europe developed a scale of itch called the Peak Pruritus Numerical Rating Scale (NRS). The scale measures the worst itch (peak pruritus) during the past 24 hours by asking patients "On a scale of 0 to 10, with 0 being 'no itch' and 10 being 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?". To ensure the scale is reliable and valid (i.e., appropriate for assessing itch in AD patients), patients were interviewed about their opinions of the scale. The scale was then implemented in three large clinical trials of adults with moderate‐to‐severe AD. Interviewed patients said that the scale provided a relevant, clear, and comprehensive assessment of itch severity. As hypothesized, scores from the Peak Pruritus NRS showed moderate‐to‐strong correlation with other measures of itch, and weak‐to‐moderate correlation with measures of AD signs (clinical symptoms). The investigators concluded that the Peak Pruritus NRS is a well‐defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate‐to‐severe AD. Linked Article: Yosipovitch et al. Br J Dermatol 2019; 181:761–769 [ABSTRACT FROM AUTHOR]

Summary: Atopic dermatitis (also called AD or eczema) is a chronic skin disease found in up to 1 in 10 adults, causing itchy rashes that may cover most of the body. Ciclosporin, an oral treatment (taken by mouth) commonly used for AD, doesn't always work and can have significant side effects. Other broadly‐acting oral medications are sometimes used, but not approved, for AD. Dupilumab is a new medication approved in many countries for adults with inadequately controlled moderate‐to‐severe AD. Dupilumab specifically targets pathways in the body that drive AD. Researchers in Europe evaluated how well dupilumab injections improved rashes, itch, and daily lives of people whose AD required ciclosporin, but for whom ciclosporin wasn't working or caused intolerable side effects, or whose medical conditions prevented its use. Among 325 participants, 110 received 300 mg dupilumab once‐weekly, 107 received it every two weeks, and 108 received placebo (dummy drug) once‐weekly. All participants used topical (applied to the skin) corticosteroids during the 16‐week study. Dupilumab improved AD rashes: at Week 0, participants’ Eczema Area and Severity Index (EASI) scores were about 31 (scale: 0–72), but by Week 16, 59% to 62% of dupilumab‐treated participants achieved 75% or greater improvement in EASI, versus 29.6% of people on placebo. Dupilumab also improved itch, other symptoms, mood, and quality of life. Conjunctivitis and injection‐site reactions were more frequent among dupilumab‐treated patients; skin infections (excluding herpes) and AD exacerbations (worsening) were more frequent with placebo. The authors conclude that dupilumab plus topical corticosteroids significantly improved AD even in adults with AD who had previously failed treatment with or were unable to use ciclosporin. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.Methods: In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.Results: We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.Conclusions: In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .). [ABSTRACT FROM AUTHOR]