Dupilumab provides favourable long‐term safety and efficacy in children aged ≥ 6 to < 12 years with uncontrolled, severe atopic dermatitis: results from an open‐label phase IIa study and subsequent phase III open‐label extension study

Background Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16‐week, randomized, placebo‐controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)‐4/IL‐13 signalling, significantly improved signs and symptoms with acceptable safety; longer‐term safety and efficacy data are lacking. Objectives To report the pharmacokinetic profile and long‐term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. Methods Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study and subsequent open‐label extension (OLE) study. Patients received single‐dose dupilumab 2 or 4 mg kg−1 followed by 8‐week pharmacokinetic sampling, then 2 or 4 mg kg−1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration–time profile and treatment‐emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP‐NRS) score. Results Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target‐mediated pharmacokinetics characterized dupilumab concentrations (week 24–48 mean serum concentrations: 2 mg kg−1, 61–77 mg L−1; 4 mg kg−1, 143–181 mg L−1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg−1, 47%; 4 mg kg−1, 56%) and AD exacerbation (29% and 13%, respectively). Single‐dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP‐NRS improved by −37%/−33% and −17%/−20% at week 2 (phase IIa) and −92%/−84% and −70%/−58% at week 52 (OLE), respectively. Conclusions These safety and efficacy results support the use of dupilumab as a continuous long‐term treatment for children aged ≥ 6 to < 12 years with severe AD

Infections in children aged 6 months to 5 years treated with dupilumab in a placebo-controlled clinical trial of moderate-to-severe atopic dermatitis

Background: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. Methods: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo, with concomitant low-potency topical corticosteroids, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. Results: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48–1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21–0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01–0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30–0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31–4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12–0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. Conclusions: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. Trial Registration: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. Infographic: [Figure not available: see fulltext.

Dupilumab Treatment Leads to Rapid and Consistent Improvement of Atopic Dermatitis in All Anatomical Regions in Patients Aged 6 Months to 5 Years

Introduction: Atopic dermatitis (AD) is heterogeneous in distribution pattern and clinical features. This analysis assessed the effect of dupilumab on the extent and severity of AD across various signs (erythema, edema/papulation, excoriation, lichenification) in different anatomical regions (head and neck, trunk, upper extremities, lower extremities) in patients aged 6 months to 5 years. Methods: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo with concomitant low-potency topical corticosteroids (TCS) every 4 weeks for 16 weeks. Changes in AD signs across anatomical regions were assessed using unweighted Eczema Area and Severity Index (EASI) body region scores. Results: Overall, 162 patients were randomized to dupilumab (n = 83) or placebo (n = 79). A significant improvement in least squares mean EASI area score was seen by week 2 in all four anatomical regions (P < 0.0001 for dupilumab vs. placebo) and sustained throughout treatment. Least squares mean EASI sign scores in erythema, excoriations, and infiltration/papulation showed significant improvement by week 2 in all regions (P < 0.001), while lichenification showed significant improvement in all regions by week 4 (P < 0.001). Conclusion: Dupilumab use with concomitant low-potency TCS treatment resulted in rapid and consistent improvement in AD signs in all anatomical regions, in patients aged 6 months to 5 years with moderate-to-severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03346434 Part B

Laboratory safety from a randomized 16-week phase III study of dupilumab in children aged 6 months to 5 years with moderate-to-severe atopic dermatitis

Background and Objective: Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab. Methods: In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided. Results: No clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal. Conclusions: These results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening. Clinical Trial Registration: ClinicalTrials.gov: NCT03346434, part

Dupilumab safety and efficacy in a phase III open-label extension trial in children 6–11 years of age with severe atopic dermatitis

Background: For children aged 6–11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. Objectives: This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). Methods: Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required. Results: Data for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response. Conclusions: Consistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6–11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit. Trial Registration: ClinicalTrials.gov Identifier NCT02612454

Laboratory safety of dupilumab in patients aged 6–11 years with severe atopic dermatitis : results from a phase III clinical trial

Background Previous studies of dupilumab in adolescents and adults with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful adverse changes in laboratory parameters. Objective The aim of this study was to assess laboratory outcomes in children aged 6–11 years with severe AD in a randomized, placebo-controlled, phase III trial of dupilumab. Methods Children aged 6–11 years with severe AD were randomized 1:1:1 to 16 weeks of dupilumab 300 mg every 4 weeks, 100 or 200 mg every 2 weeks, or matching placebo, all with concomitant topical corticosteroids (TCS). Blood samples were collected at baseline and Weeks 4, 8, and 16; urine samples were collected at baseline and Weeks 4 and 16. Results Of 367 patients enrolled in the study, 362 were included in the safety analysis, 351 completed study treatment, and 4 withdrew due to treatment-emergent adverse events not related to laboratory abnormalities. Both dupilumab + TCS groups showed overall trends toward increases in mean blood levels of eosinophils and alkaline phosphatase, and decreases in mean blood levels of platelets, neutrophils, and lactate dehydrogenase levels, without corresponding mean changes in the placebo + TCS group. None of these changes were associated with symptoms or clinically meaningful adverse outcomes, and none led to treatment modification. No clinically significant changes or trends were observed for other measured laboratory parameters. Conclusion There were no clinically meaningful adverse changes in routine laboratory parameters attributable to treatment with dupilumab + TCS. Changes in platelet counts and lactate dehydrogenase levels likely reflect reduced inflammation. These results confirm similar findings in adults and adolescents, and suggest that there is no need for routine laboratory monitoring of children aged 6–11 years treated with dupilumab + TCS for severe AD. Trial Registration ClinicalTrials.gov Identifier: NCT03345914

The Imaging Magnetograph eXperiment (IMaX) for the Sunrise balloon-borne solar observatory

The Imaging Magnetograph eXperiment (IMaX) is a spectropolarimeter built by four institutions in Spain that flew on board the Sunrise balloon-borne telesocope in June 2009 for almost six days over the Arctic Circle. As a polarimeter IMaX uses fast polarization modulation (based on the use of two liquid crystal retarders), real-time image accumulation, and dual beam polarimetry to reach polarization sensitivities of 0.1%. As a spectrograph, the instrument uses a LiNbO3 etalon in double pass and a narrow band pre-filter to achieve a spectral resolution of 85 mAA. IMaX uses the high Zeeman sensitive line of Fe I at 5250.2 AA and observes all four Stokes parameters at various points inside the spectral line. This allows vector magnetograms, Dopplergrams, and intensity frames to be produced that, after reconstruction, reach spatial resolutions in the 0.15-0.18 arcsec range over a 50x50 arcsec FOV. Time cadences vary between ten and 33 seconds, although the shortest one only includes longitudinal polarimetry. The spectral line is sampled in various ways depending on the applied observing mode, from just two points inside the line to 11 of them. All observing modes include one extra wavelength point in the nearby continuum. Gauss equivalent sensitivities are four Gauss for longitudinal fields and 80 Gauss for transverse fields per wavelength sample. The LOS velocities are estimated with statistical errors of the order of 5-40 m/s. The design, calibration and integration phases of the instrument, together with the implemented data reduction scheme are described in some detail.Comment: 17 figure

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

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

Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: a randomized, double-blinded, placebo-controlled phase 3 trial

Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6–11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300mg dupilumab every 4 weeks (300mg-q4w), a weight-based regimen of dupilumab every 2 weeks (100mg-q2w, baseline weight <30kg; 200mg-q2w, ≥30kg), or placebo; with concomitant medium-potency TCS. Results Both the q4w and q2w dupilumab+TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QoL) versus placebo+TCS in all prespecified endpoints. For q4w/q2w/placebo, 32.8%/29.5%/11.4% of patients achieved Investigator’s Global Assessment scores of 0/1; 69.7%/67.2%/26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%/58.3%/12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300mg-q4w in children <30kg and 200mg-q2w in children ≥30kg. Conjunctivitis and injection-site reactions were more common with dupilumab+TCS than placebo+TCS. Limitations Short-term 16-week treatment period; severe AD only. Conclusion Dupilumab+TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QoL